Pyrazolone-Fused Pyrimidine Compound, Preparation Method for Same and Applications Thereof

ABSTRACT

Disclosed are a pyrazolone-fused pyrimidine compound, a preparation method for same and applications thereof. Provided in the present invention is the pyrazolone-fused pyrimidine compound as represented by formula (II). The compound has improved inhibitory activity with respect to WEE1 kinase.

The present application claims the priority of Chinese patentapplication 201910579671.0 filed on Jun. 28, 2019. The contents of theChinese patent application are incorporated herein by reference in theirentireties.

TECHNICAL FIELD

The present disclosure relates to a pyrazolone-fused pyrimidinecompound, a preparation method therefor and an application thereof.

BACKGROUND

Cell cycle is closely related to DNA damage repair process. Cell cyclerefers to the whole process of cell division, which is divided into twostages: interphase and mitotic phase (M). Cell cycle checkpoint is a keypoint to regulate the cell cycle, its main function is to ensure thatevery event in the cycle can be completed on time and orderly, and toadjust the cell state to adapt to the external environment. The maincheckpoints of cells are as follows: 1) G1/S checkpoint, which is calledR (restriction) point in mammals and controls cells from static G1 phaseto DNA synthesis phase; 2) S-phase checkpoint: whether DNA replicationis completed; 3) G2/M checkpoint: it is the control point that regulatesthe cell to enter the division stage; 4) middle-late checkpoint: alsocalled spindle assembly checkpoint, if the centromere is not connectedto the spindle correctly, it will cause the interruption of cell cycle.If there is abnormality in some processes of cell division cycle, suchas DNA damage, the checkpoint will sense in time and start repair. P53protein is an important protein that regulates G1 checkpoint, when DNAis damaged, P53 protein prevents cells from entering S phase andactivates DNA repair mechanism, which is very important for maintainingthe integrity of cell genome. However, since P53 mutation often existsin tumor cells, which makes G1 checkpoint defective, therefore, theregulation of cell division cycle in P53 mutated cells depends on G2/Mcheckpoint. WEE1 kinase is a cell cycle regulatory protein, which canregulate the phosphorylation state of cyclin-dependent kinase 1 (CDK1),thus regulating the activity of CDK1 and cyclin B complex, realizing theregulation of cell cycle, and playing an important role in regulatingDNA damage checkpoints. WEE1 is a key gene in G2/M phase block, plays animportant monitoring role, and is overexpressed in some cancers,inhibition or downregulation of WEE1 kinase may trigger mitoticcatastrophe, so WEE1 kinase inhibitors have a key role in anticancertherapy and have become a hot spot for the development of anticancerdrugs.

International patent applications WO2019037678, WO2019028008,WO2018133829, WO2010098367, WO2010067886, WO2008115742, WO2008115738,WO2007126122, WO2007126128 WO2004007499 and others have disclosed partof small molecule WEE1 kinase inhibitors, but there are no smallmolecule WEE1 kinase inhibitors on the market, and there is still a needin the art to develop new WEE1 kinase inhibitors with good anticanceractivity and high safety.

Content of the Present Invention

The technical problem to be solved by the present disclosure is that theexisting compounds with inhibitory activity against WEE1 kinase have asingle structure, therefore, the present disclosure provides apyrazolone-fused pyrimidine compound, a preparation method therefor andan application thereof, and the compound has a better inhibitoryactivity against WEE1 kinase.

The present disclosure provides a pyrazolone-fused pyrimidine compoundrepresented by formula II, a pharmaceutically acceptable salt thereof, asolvate thereof, a solvate of the pharmaceutically acceptable saltthereof, a metabolite thereof or a prodrug thereof:

wherein, A is C₃-C₂₀ cycloalkyl substituted by one or two R¹;

X is CH or N;

R¹ is independently halogen, —OR¹⁻¹, —SR¹⁻², —CN, —NR¹⁻³R¹⁻⁴,—C(═O)R¹⁻⁵, —C(═NR¹⁻⁶)R¹⁻⁷, ═N—O—R¹⁻⁹ (wherein “=” refers to thesubstitution of two hydrogens on the methylene of the cycloalkyl) or“C₂-C₇ alkenyl, C₂-C₈ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻⁸;

R¹⁻¹ is independently “C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇ heteroaryl”optionally substituted by one, two or three R¹⁻¹⁻¹;

R¹⁻¹⁻¹ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻¹⁻¹⁻¹”; R¹⁻¹⁻¹⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻² is independently hydrogen, “C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, orC₁-C₇ heteroaryl” optionally substituted by one, two or three R¹⁻²⁻¹;

R¹⁻²⁻¹ is independently hydrogen, halogen, hydroxyl, amino, mercapto,cyano, C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻²⁻¹⁻¹”; R¹⁻²⁻¹⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶, —S(═O)₂NR¹⁻³⁻⁷R¹⁻³⁻⁸, —C(═O)NR¹⁻³⁻⁹R¹⁻³⁻¹⁰ or“C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻³⁻¹¹;

or, R¹⁻³ and R¹⁻⁴ together with the nitrogen atom they are attached toform a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻³⁻¹²; one or more methylenes in the C₃-C₁₄ heterocycloalkyl areoptionally and independently substituted by oxygen atom, sulfur atom,sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻¹³)—; R¹⁻³⁻¹³ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻¹ and R¹⁻³⁻² are independently “C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl or C₆-C₁₀ aryl”optionally substituted by one or two R¹⁻³⁻¹⁻¹; R¹⁻³⁻¹⁻¹ is independentlyC₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻³ is independently hydrogen, —CN, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇alkynyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻⁵, R¹⁻³⁻⁶, R¹⁻³⁻⁷, R¹⁻³⁻⁸, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰ are independentlyhydrogen, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl or C₃-C₁₄cycloalkyl;

or, R¹⁻³⁻⁵ and R¹⁻³⁻⁶ together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻³⁻⁵⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom, sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻⁵⁻²)—;R¹⁻³⁻⁵⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻⁵⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

or, R¹⁻³⁻⁷ and R¹⁻³⁻⁸ together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻³⁻⁷⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom, sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻⁷⁻²)—;R¹⁻³⁻⁷⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻⁷⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

or, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰ together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻³⁻⁹⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom, sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻⁹⁻²)—;R¹⁻³⁻⁹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻⁹⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻¹¹ is independently halogen, hydroxyl, amino, mercapto, cyano,C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻³⁻¹¹⁻¹”. R¹⁻³⁻¹¹⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻¹² is independently halogen, hydroxyl, amino, mercapto, cyano,C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or amino substituted by one or two R¹⁻³⁻¹²⁻¹; R¹⁻³⁻¹²⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁵ is independently hydrogen, —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or “C₁-C₇ alkyl,C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻⁵⁻⁴;

R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl, C₂-C₇alkenyl, C₂-C₇ alkynyl or C₃-C₁₄ cycloalkyl;

or, R¹⁻⁵⁻¹ and R¹⁻⁵⁻² together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻⁵⁻¹⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom, sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻⁵⁻¹⁻²)—;R¹⁻⁵⁻¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻¹⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁵⁻³ is independently hydrogen, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl orC₁-C₇ heteroaryl;

R¹⁻⁵⁻⁴ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻⁵⁻⁴⁻¹”. R¹⁻⁵⁻⁴⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁶ is independently hydrogen, —CN, —OH or “C₁-C₇ alkyl, C₂-C₇ alkenyl,C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl,or C₁-C₇ heteroaryl” optionally substituted by one, two or three R¹⁻⁶⁻¹;

R¹⁻⁶⁻¹ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or amino substituted by one or two R¹⁻⁶⁻¹⁻¹; R¹⁻⁶⁻¹⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁷ is independently hydrogen, —OR¹⁻⁷⁻¹, —NR¹⁻⁷⁻²R¹⁻⁷⁻³ or “C₁-C₇alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻⁷⁻⁴;

R¹⁻⁷⁻¹ is independently hydrogen, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl orC₁-C₇ heteroaryl;

R¹⁻⁷⁻² and R¹⁻⁷⁻³ are independently C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇alkynyl or C₃-C₁₄ cycloalkyl;

or, R¹⁻⁷⁻² and R¹⁻⁷⁻³ together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻⁷⁻²⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom, sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻⁷⁻²⁻²)—;R¹⁻⁷⁻²⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁷⁻²⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁷⁻⁴ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻⁷⁻⁴⁻¹”. R¹⁻⁷⁻⁴⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁸ is independently oxo, halogen, —OH, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻⁸⁻¹”; R¹⁻⁸⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁹ is independently hydrogen or C₁-C₇ alkyl;

R² is —OR²⁻¹, cyano, carboxyl; or “C₂-C₇ alkyl, C₃-C₁₄ cycloalkyl orC₃-C₁₄ heterocycloalkyl” optionally substituted by one, two or threeR²⁻²;

R²⁻¹ is C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl;

R²⁻² is independently halogen, hydroxyl, amino, C₁-C₇ alkyl, C₁-C₇alkoxy, C₃-C₁₄ cycloalkyl or C₃-C₁₄ heterocycloalkyl;

in any one of the above cases, the heteroatoms in the C₃-C₁₄heterocycloalkyl, C₁-C₇ heteroaryl are independently selected from oneor more of boron, silicon, oxygen, sulfur, selenium, nitrogen andphosphorus; the number of heteroatoms is independently 1, 2, 3 or 4.

In a certain scheme, some substituents in the pyrazolone-fusedpyrimidine compound represented by formula II, the pharmaceuticallyacceptable salt thereof, the solvate thereof, the solvate of thepharmaceutically acceptable salt thereof, the metabolite thereof or theprodrug thereof may further have the following definitions, and thedefinitions of substituents not involved below are as described in anyof the above schemes (hereinafter referred to as “in a certain scheme”):

When A is C₃-C₂₀ cycloalkyl substituted by one or two R¹, the C₃-C₂₀cycloalkyl is for example C₃-C₂₀ monocyclic cycloalkyl, C₃-C₂₀ spirocycloalkyl, C₃-C₂₀ fused cycloalkyl or C₃-C₂₀ bridged cycloalkyl.

The C₃-C₂₀ monocyclic cycloalkyl is for example C₃-C₆ monocycliccycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, for example cyclohexyl.

The C₃-C₂₀ bridged cycloalkyl is for example C₅-C₈ bridged cycloalkyl,for example

In a certain scheme:

When A is C₃-C₂₀ cycloalkyl substituted by one or two R¹, the C₃-C₂₀cycloalkyl is for example C₃-C₂₀ saturated cycloalkyl.

In a certain scheme:

When A is C₃-C₂₀ cycloalkyl substituted by one R¹, the A is for example

the

is for example

for example,

the ratio of

is 1:1”.

the

is for example

for example,

the ratio of

is 1:1”.

In a certain scheme:

When R¹ is independently C₃-C₁₄ heterocycloalkyl, the C₃-C₁₄heterocycloalkyl is for example C₃-C₁₄ monocyclic heterocycloalkyl,C₃-C₁₄ spiro heterocycloalkyl, C₃-C₁₄ fused heterocycloalkyl or C₃-C₁₄bridged heterocycloalkyl.

The C₃-C₁₄ monocyclic heterocycloalkyl is, for example, “C₃-C₉monocyclic heterocycloalkyl having one or two heteroatoms selected fromone or two of N, O and S”, for example, “C₃-C₅ monocyclicheterocycloalkyl having one or two heteroatoms selected from one or twoof N, O and S”, for example, “C₃-C₅ monocyclic heterocycloalkyl havingone or two heteroatoms selected from one or two of N, O and S” and whichis connected to a benzene ring by a nitrogen atom, for example,azetidinyl, morpholinyl, piperidinyl or piperazinyl.

The azetidinyl is for example

The morpholinyl is for example

The piperidinyl is for example

The piperazinyl is for example

In a certain scheme:

When R¹ is independently C₃-C₁₄ heterocycloalkyl, the heteroatom of theC₃-C₁₄ heterocycloalkyl may not be substituted.

In a certain scheme:

When R¹ is independently C₃-C₁₄ heterocycloalkyl, the methylene in theC₃-C₁₄ heterocycloalkyl may not be substituted.

In a certain scheme:

When R¹ is independently C₃-C₁₄ heterocycloalkyl substituted by oneR¹⁻⁸, the C₃-C₁₄ heterocycloalkyl is for example C₃-C₁₄ monocyclicheterocycloalkyl, C₃-C₁₄ spiro heterocycloalkyl, C₃-C₁₄ fusedheterocycloalkyl or C₃-C₁₄ bridged heterocycloalkyl.

The C₃-C₁₄ monocyclic heterocycloalkyl is, for example, “C₃-C₉monocyclic heterocycloalkyl having one or two heteroatoms selected fromone or two of N, O and S”, for example, “C₃-C₅ monocyclicheterocycloalkyl having one or two heteroatoms selected from one or twoof N, O and S”, for example, “C₃-C₅ monocyclic heterocycloalkyl havingone or two heteroatoms selected from one or two of N, O and S” and whichis connected to a benzene ring by a nitrogen atom, for example,azetidinyl,

morpholinyl, piperidinyl or piperazinyl.

The azetidinyl is for example

The morpholinyl is for example

The piperidinyl is for example

The piperazinyl is for example

In a certain scheme:

When R¹ is independently C₃-C₁₄ heterocycloalkyl substituted by oneR¹⁻⁸, the heteroatom of the C₃-C₁₄ heterocycloalkyl may not besubstituted except R¹⁻⁸.

In a certain scheme:

When R¹ is independently C₃-C₁₄ heterocycloalkyl substituted by oneR¹⁻⁸, the methylene in the C₃-C₁₄ heterocycloalkyl may not besubstituted.

In a certain scheme:

When R¹ is independently C₃-C₁₄ heterocycloalkyl substituted by oneR¹⁻⁸, the C₃-C₁₄ heterocycloalkyl substituted by one R¹⁻⁸ may be

In a certain scheme:

When R¹⁻³ and R¹⁻⁴ are independently C₁-C₇ alkyl, the C₁-C₇ alkyl is forexample C₁-C₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl.

In a certain scheme:

When R¹⁻³⁻¹ is independently C₁-C₇ alkyl, the C₁-C₇ alkyl is for exampleC₁-C₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl.

In a certain scheme:

When R¹⁻³⁻² is C₃-C₁₄ cycloalkyl, the C₃-C₁₄ cycloalkyl is for exampleC₃-C₁₄ monocyclic cycloalkyl, for example C₃-C₆ monocyclic cycloalkyl,for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, forexample cyclopropyl.

In a certain scheme:

When R¹⁻³⁻² is C₃-C₁₄ cycloalkyl, the C₃-C₁₄ cycloalkyl is for exampleC₃-C₁₄ saturated cycloalkyl.

In a certain scheme:

When R¹⁻⁵ is independently C₃-C₁₄ heterocycloalkyl, the C₃-C₁₄heterocycloalkyl is for example C₃-C₁₄ monocyclic heterocycloalkyl,C₃-C₁₄ spiro heterocycloalkyl, C₃-C₁₄ fused heterocycloalkyl or C₃-C₁₄bridged heterocycloalkyl.

The C₃-C₁₄ monocyclic heterocycloalkyl is, for example, “C₃-C₉monocyclic heterocycloalkyl having one or two heteroatoms selected fromone or two of N, O and S”, for example, “C₃-C₅ monocyclicheterocycloalkyl having one or two heteroatoms selected from one or twoof N, O and S”, for example, “C₃-C₅ monocyclic heterocycloalkyl havingone or two heteroatoms selected from one or two of N, O and S” and whichis connected to a benzene ring by a nitrogen atom, for example,azetidinyl.

The azetidinyl is for example

In a certain scheme:

When R¹⁻⁵ is independently C₃-C₁₄ heterocycloalkyl, the heteroatom ofthe C₃-C₁₄ heterocycloalkyl may not be substituted.

In a certain scheme:

When R¹⁻⁵ is independently C₃-C₁₄ heterocycloalkyl, the methylene in theC₃-C₁₄ heterocycloalkyl may not be substituted.

In a certain scheme:

When R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently C₁-C₇ alkyl, the C₁-C₇ alkyl isfor example C₁-C₃ alkyl, for example methyl, ethyl, n-propyl orisopropyl.

In a certain scheme:

When R¹⁻¹⁻¹ and R¹⁻⁵⁻² are independently C₃-C₁₄ cycloalkyl, the C₃-C₁₄cycloalkyl is for example C₃-C₁₄ monocyclic cycloalkyl, C₃-C₁₄ spirocycloalkyl, C₃-C₁₄ fused cycloalkyl or C₃-C₁₄ bridged cycloalkyl.

The C₃-C₁₄ monocyclic cycloalkyl is for example C₃-C₆ monocycliccycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, for example cyclobutyl, cyclopentyl or cyclohexyl.

The C₃-C₁₄ bridged cycloalkyl is for example C₅-C₅ bridged cycloalkyl,for example

In a certain scheme:

When R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently C₃-C₁₄ cycloalkyl, the C₃-C₁₄cycloalkyl is for example C₃-C₁₄ saturated cycloalkyl.

In a certain scheme:

When R¹⁻⁵⁻³ is independently C₁-C₇ alkyl, the C₁-C₇ alkyl is for exampleC₁-C₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl.

In a certain scheme:

When R¹⁻⁹ is independently C₁-C₇ alkyl, the C₁-C₇ alkyl is for exampleC₁-C₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl.

In a certain scheme:

When R² is C₂-C₇ alkyl optionally substituted by one, two or three R²⁻²,the C₂-C₇ alkyl is for example C₂-C₄ alkyl, for example ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for exampleisopropyl.

In a certain scheme:

When R² is C₂-C₇ alkyl substituted by one R²⁻², R²⁻² is hydroxyl; theC₂-C₇ alkyl substituted by one R²⁻² is for example

In a certain scheme:

When R² is C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R²⁻², the C₃-C₁₄ heterocycloalkyl is for example C₃-C₁₄ monocyclicheterocycloalkyl, C₃-C₁₄ spiro heterocycloalkyl, C₃-C₁₄ fusedheterocycloalkyl or C₃-C₁₄ bridged heterocycloalkyl.

The C₃-C₁₄ monocyclic heterocycloalkyl is, for example, “C₃-C₉monocyclic heterocycloalkyl having one or two heteroatoms selected fromone or two of N, O and S”, for example, “C₃-C₅ monocyclicheterocycloalkyl having one or two heteroatoms selected from one or twoof N, O and S”, for example, “C₃-C₅ monocyclic heterocycloalkyl havingone or two heteroatoms selected from one or two of N, O and S” and whichis connected to a benzene ring by a nitrogen atom, for example,oxetanyl.

The morpholinyl oxetanyl is for example oxetan-3-yl.

In a certain scheme:

When R² is C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R²⁻², the heteroatom of the C₃-C₁₄ heterocycloalkyl may not besubstituted except R²⁻².

In a certain scheme:

When R² is C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R²⁻², the methylene in the C₃-C₁₄ heterocycloalkyl may not besubstituted.

In a certain scheme:

When R² is C₃-C₁₄ heterocycloalkyl substituted by one R²⁻², R²⁻² ishalogen or hydroxyl; the C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²is for example

In a certain scheme:

The ratio of each isomer in the pyrazolone-fused pyrimidine compoundrepresented by formula II may be equal, for example, racemate.

In a certain scheme:

The atoms in the pyrazolone-fused pyrimidine compound represented byformula II, the pharmaceutically acceptable salt thereof, the solvatethereof, the solvate of the pharmaceutically acceptable salt thereof,the metabolite thereof or the prodrug thereof may all exist in theirnatural abundance.

In a certain scheme:

A is C₃-C₂₀ cycloalkyl substituted by one R¹.

In a certain scheme:

A is

substituted by one or two R¹”.

In a certain scheme:

A is

In a certain scheme:

R¹ is independently halogen, —CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵,—C(═NR¹⁻⁶)R¹⁻⁷, ═N—O—R¹⁻⁹ or “C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻⁸.

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶, —S(═O)₂NR¹⁻³⁻⁷R¹⁻³⁻⁸, —C(═O)NR¹⁻³⁻⁹R¹⁻³⁻¹⁰ or“C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl orC₁-C₇ heteroaryl” optionally substituted by one, two or three R¹⁻³⁻¹¹.

R¹⁻³⁻¹ and R¹⁻³⁻² are independently “C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl or C₆-C₁₀ aryl” optionally substituted by one ortwo R¹⁻³⁻¹⁻¹”; R¹⁻³⁻¹⁻¹ is independently C₁-C₇ alkyl;

R¹⁻³⁻³ is independently hydrogen;

R¹⁻³⁻¹, R¹⁻³⁻⁶, R¹⁻³⁻⁷, R¹⁻³⁻¹, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰ are independentlyhydrogen, C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻¹¹ is independently halogen, hydroxyl, amino, mercapto, cyano,C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻³⁻¹¹⁻¹”; R¹⁻³⁻¹¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁵ is independently hydrogen, —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or “C₁-C₇alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇heteroaryl” optionally substituted by one, two or three R¹⁻⁵⁻⁴;

R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁵⁻³ is independently hydrogen, C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl;

R¹⁻⁵⁻⁴ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁵⁻⁴⁻¹”; R¹⁻⁵⁻⁴⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁶ is independently hydrogen, —CN, —OH;

R¹⁻⁷ is independently hydrogen, —NR¹⁻⁷⁻²R¹⁻⁷⁻³;

R¹⁻⁷⁻² and R¹⁻⁷⁻³ are independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

or, R¹⁻⁷⁻² and R¹⁻⁷⁻³ together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻⁷⁻²⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom; R¹⁻⁷⁻²⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁸ is independently oxo, halogen, —OH, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁸⁻¹”; R¹⁻⁸⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁹ is independently hydrogen or C₁-C₇ alkyl.

In a certain scheme:

R¹ is independently halogen, —CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, —C(═NR¹⁻⁶)R¹⁻⁷or “C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇heteroaryl” optionally substituted by one, two or three R¹⁻⁸;

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶, —S(═O)₂NR¹⁻³⁻⁷R¹⁻³⁻⁸, —C(═O)NR¹⁻³⁻⁹R¹⁻³⁻¹⁰ or“C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl orC₁-C₇ heteroaryl” optionally substituted by one, two or three R¹⁻³⁻¹¹;

R¹⁻³⁻¹ and R¹⁻³⁻² are independently “C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl or C₆-C₁₀ aryl” optionally substituted by one ortwo R¹⁻³⁻¹⁻¹; R¹⁻³⁻¹-1 is independently C₁-C₇ alkyl;

R¹⁻³⁻³ is independently hydrogen;

R¹⁻³⁻⁵, R¹⁻³⁻⁶, R¹⁻³⁻⁷, R¹⁻³⁻⁸, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰ are independentlyC₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻¹¹ is independently halogen, hydroxyl, amino, mercapto, cyano,C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻³⁻¹¹-1”; R¹⁻³⁻¹¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁵ is independently hydrogen, —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or “C₁-C₇alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇heteroaryl” optionally substituted by one, two or three R¹⁻⁵⁻⁴;

R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁵⁻³ is independently hydrogen, C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl;

R¹⁻⁵⁻⁴ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁵⁻⁴⁻¹”; R¹⁻⁵⁻⁴⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁶ is independently hydrogen, —CN, —OH;

R¹⁻⁷ is independently hydrogen, —NR¹⁻⁷⁻²R¹⁻⁷⁻³;

R¹⁻⁷⁻² and R¹⁻⁷⁻³ are independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

or, R¹⁻⁷⁻² and R¹⁻⁷⁻³ together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻⁷⁻²⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom; R¹⁻⁷⁻²⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁸ is independently halogen, —OH, amino, mercapto, cyano, C₁-C₇ alkyl,C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁸⁻¹”; R¹⁻⁸⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl.

In a certain scheme:

R¹ is independently cyano, halogen, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵,—C(═NR¹⁻⁶)R¹⁻⁷, ═N—O—R¹⁻⁹, C₁-C₇ heteroaryl or “C₃-C₁₄ heterocycloalkyloptionally substituted by one R¹⁻⁸”.

In a certain scheme:

R¹ is independently cyano, halogen, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵,—C(═NR¹⁻⁶)R¹⁻⁷, C₁-C₇ heteroaryl or C₃-C₁₄ heterocycloalkyl.

In a certain scheme:

R¹ is —CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, ═N—O—R¹⁻⁹, or “C₃-C₁₄heterocycloalkyl optionally substituted by one R¹⁻⁸”.

In a certain scheme:

R¹ is independently —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵ or C₃-C₁₄ heterocycloalkyl.

In a certain scheme:

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶ or C₁-C₇ alkyl;

R¹⁻³⁻¹ and R¹⁻³⁻² are independently C₁-C₇ alkyl, or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻³ is hydrogen;

R¹⁻³⁻⁵ and R¹⁻³⁻⁶ are hydrogen.

In a certain scheme:

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹ or C₁-C₇ alkyl;R¹⁻³⁻¹ is independently C₁-C₇ alkyl.

In a certain scheme:

R¹⁻⁵ is independently —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄heterocycloalkyl; R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ is independently hydrogen or C₁-C₇alkyl.

In a certain scheme:

R¹⁻⁵ is independently —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄heterocycloalkyl; R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ is hydrogen.

In a certain scheme:

R¹⁻⁸ is independently oxo.

In a certain scheme:

R¹⁻⁹ is independently hydrogen or C₁-C₇ alkyl.

In a certain scheme:

R² is “C₂-C₇ alkyl, C₃-C₁₄ cycloalkyl or C₃-C₁₄ heterocycloalkyl”optionally substituted by one, two or three R²⁻²;

R²⁻² is independently halogen or hydroxyl.

In a certain scheme:

R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”;R²⁻² is halogen or hydroxyl.

In a certain scheme:

R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”;R²⁻² is hydroxyl.

In a certain scheme:

R² is

In a certain scheme:

X is N.

In a certain scheme:

R¹ is ═N—O—R¹⁻⁹; R¹⁻⁹ is independently hydrogen or C₁-C₇ alkyl.

In a certain scheme:

R¹⁻³⁻⁵, R¹⁻³⁻⁶, R¹⁻³⁻⁷, R¹⁻³⁻⁸, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰ are hydrogen.

In a certain scheme:

A is

substituted by one or two R¹”;

X is CH or N;

R¹ is independently halogen, —CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵,—C(═NR¹⁻⁶)R¹⁻⁷, ═N—O—R¹⁻⁹ or “C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻⁸.

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶, —S(═O)₂NR¹⁻³⁻⁷R¹⁻³⁻⁸, —C(═O)NR¹⁻³⁻⁹R¹⁻³⁻¹⁰ or“C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl orC₁-C₇ heteroaryl” optionally substituted by one, two or three R¹⁻³⁻¹¹;

R¹⁻³⁻¹ and R¹⁻³⁻² are independently “C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl or C₆-C₁₀ aryl” optionally substituted by one ortwo R¹⁻³⁻¹⁻¹; R¹⁻³⁻¹⁻¹ is independently C₁-C₇ alkyl;

R¹⁻³⁻³ is independently hydrogen;

R¹⁻³⁻⁵, R¹⁻³⁻⁶, R¹⁻³⁻⁷, R¹⁻³⁻⁸, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰ are independentlyhydrogen, C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻¹¹ is independently halogen, hydroxyl, amino, mercapto, cyano,C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻³⁻¹¹⁻¹”; R¹⁻³⁻¹¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁵ is independently hydrogen, —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or “C₁-C₇alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇heteroaryl” optionally substituted by one, two or three R¹⁻⁵⁻⁴;

R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁵⁻³ is independently hydrogen, C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl;

R¹⁻⁵⁻⁴ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁵⁻⁴⁻¹”; R¹⁻⁵⁻⁴⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁶ is independently hydrogen, —CN, —OH;

R¹⁻⁷ is independently hydrogen, —NR¹⁻⁷⁻²R¹⁻⁷⁻³;

R¹⁻⁷⁻² and R¹⁻⁷⁻³ are independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

or, R¹⁻⁷⁻² and R¹⁻⁷⁻³ together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻⁷⁻²⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom; R¹⁻⁷⁻²⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁸ is independently oxo, halogen, —OH, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁸⁻¹”; R¹⁻⁸⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁹ is independently hydrogen or C₁-C₇ alkyl;

R² is “C₂-C₇ alkyl, C₃-C₁₄ cycloalkyl or C₃-C₁₄ heterocycloalkyl”optionally substituted by one, two or three R²⁻²;

R²⁻² is independently halogen or hydroxyl;

in any one of the above cases, the heteroatoms in the C₃-C₁₄heterocycloalkyl, C₁-C₇ heteroaryl are independently selected from oneor more of boron, silicon, oxygen, sulfur, selenium, nitrogen andphosphorus; the number of heteroatoms is independently 1, 2, 3 or 4.

In a certain scheme:

A is C₃-C₂₀ cycloalkyl substituted by one or two R¹;

X is CH or N;

R¹ is independently cyano, halogen, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵,—C(═NR¹⁻⁶)R¹⁻⁷, ═N—O—R¹⁻⁹, C₁-C₇ heteroaryl or “C₃-C₁₄ heterocycloalkyl”optionally substituted by one R¹⁻⁸.

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³-3)NR¹⁻³⁻⁵R¹⁻³⁻⁶ or C₁-C₇ alkyl;

R¹⁻³⁻¹ and R¹⁻³⁻² are independently C₁-C₇ alkyl, or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻³ is hydrogen;

R¹⁻³⁻⁵ and R¹⁻³⁻⁶ are hydrogen;

R¹⁻⁵ is independently —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄heterocycloalkyl; R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ is independently hydrogen or C₁-C₇alkyl;

R¹⁻⁸ is independently oxo;

R¹⁻⁹ is independently hydrogen or C₁-C₇ alkyl;

R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”;R²⁻² is halogen or hydroxyl.

In a certain scheme:

A is C₃-C₂₀ cycloalkyl substituted by one R¹;

X is CH or N;

R¹ is —CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, ═N—O—R¹⁻⁹, or “C₃-C₁₄heterocycloalkyl” optionally substituted by one R¹⁻⁸.

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶ or C₁-C₇ alkyl;

R¹⁻³⁻¹ and R¹⁻³⁻² are independently C₁-C₇ alkyl, or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻³ is hydrogen;

R¹⁻³⁻⁵ and R¹⁻³⁻⁶ are hydrogen;

R¹⁻⁵ is —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄ heterocycloalkyl;

R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁵⁻³ is independently hydrogen or C₁-C₇ alkyl;

R¹⁻⁸ is independently oxo;

R¹⁻⁹ is independently hydrogen or C₁-C₇ alkyl;

R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”;R²⁻² is hydroxyl.

In a certain scheme:

A is C₃-C₂₀ cycloalkyl substituted by one R¹;

X is CH or N;

R¹ is —CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, ═N—O—R¹⁻⁹, or “C₃-C₁₄heterocycloalkyl” optionally substituted by one R¹⁻⁸.

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³-3)NR¹⁻³⁻⁵R¹⁻³⁻⁶ or C₁-C₇ alkyl;

R¹⁻³⁻¹ and R¹⁻³⁻² are independently C₁-C₇ alkyl, or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻³ is hydrogen;

R¹⁻³⁻⁵ and R¹⁻³⁻⁶ are hydrogen;

R¹⁻⁵ is —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄ heterocycloalkyl;

R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁵⁻³ is hydrogen;

R¹⁻⁸ is independently oxo;

R¹⁻⁹ is independently hydrogen or C₁-C₇ alkyl;

R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”;R²⁻² is hydroxyl.

In a certain scheme:

A is

X is CH or N;

R¹ is —CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, ═N—O—R¹⁻⁹, or “C₃-C₁₄heterocycloalkyl” optionally substituted by one R¹⁻⁸.

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶ or C₁-C₇ alkyl;

R¹⁻³⁻¹ and R¹⁻³⁻² are independently C₁-C₇ alkyl, or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻³ is hydrogen;

R¹⁻³⁻⁵ and R¹⁻³⁻⁶ are hydrogen;

R¹⁻⁵ is —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄ heterocycloalkyl; R¹⁻⁵⁻¹ andR¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;R¹⁻⁵⁻³ is hydrogen or C₁-C₇ alkyl;

R¹⁻⁸ is independently oxo;

R¹⁻⁹ is independently hydrogen or C₁-C₇ alkyl;

R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”;R²⁻² is hydroxyl.

In a certain scheme:

A is

X is CH or N;

R¹ is independently —CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, ═N—O—R¹⁻⁹, or “C₃-C₁₄heterocycloalkyl” optionally substituted by one R¹⁻⁸.

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶ or C₁-C₇ alkyl;

R¹⁻³⁻¹ and R¹⁻³⁻² are independently C₁-C₇ alkyl, or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻³ is hydrogen;

R¹⁻³⁻⁵ and R¹⁻³⁻⁶ are hydrogen;

R¹⁻⁵ is independently —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³, or C₃-C₁₄heterocycloalkyl;

R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl, or C₃-C₁₄cycloalkyl;

R¹⁻⁵⁻³ is independently hydrogen or C₁-C₇ alkyl;

R¹⁻⁸ is independently oxo;

R¹⁻⁹ is independently hydrogen or C₁-C₇ alkyl;

R² is

In a certain scheme, the pyrazolone-fused pyrimidine compoundrepresented by formula II may be a pyrazolone-fused pyrimidine compoundrepresented by formula I:

wherein, A is C₃-C₂₀ cycloalkyl substituted by one or two R¹;

R¹ is independently halogen, —OR¹⁻¹, —SR¹⁻², —CN, —NR¹⁻³R¹⁻⁴,—C(═O)R¹⁻⁵, —C(═NR¹⁻⁶)R¹⁻⁷ or “C₂-C₇ alkenyl, C₂-C₈ alkynyl, C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl”optionally substituted by one, two or three R¹⁻⁸;

R¹⁻¹ is independently “C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇ heteroaryl”optionally substituted by one, two or three R¹⁻¹⁻¹;

R¹⁻¹⁻¹ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻¹⁻¹⁻¹”; R¹⁻¹⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻² is independently “C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇ heteroaryl”optionally substituted by one, two or three R¹⁻²⁻¹;

R¹⁻²⁻¹ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻²⁻¹⁻¹”, R¹⁻²⁻¹⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶, —S(═O)₂NR¹⁻³⁻⁷R¹⁻³⁻⁸, —C(═O)NR¹⁻³⁻⁹R¹⁻³⁻¹⁰ or“C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻³⁻¹¹;

or, R¹⁻³ and R¹⁻⁴ together with the nitrogen atom they are attached toform a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻³⁻¹²; one or more methylenes in the C₃-C₁₄ heterocycloalkyl areoptionally and independently substituted by oxygen atom, sulfur atom,sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻¹³)—; R¹⁻³⁻¹³ isindependently a C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻¹ and R¹⁻³⁻² are independently “C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl or C₆-C₁₀ aryloptionally substituted by one or two R¹⁻³⁻¹⁻¹”; R¹⁻³⁻¹⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻³ is independently hydrogen, —CN, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇alkynyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻⁵, R¹⁻³⁻⁶, R¹⁻³⁻⁷, R¹⁻³⁻⁸, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰ are independentlyC₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl or C₃-C₁₄ cycloalkyl;

or, R¹⁻³⁻⁵ and R¹⁻³⁻⁶ together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻³⁻⁵-1; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom, sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻⁵⁻²)—;R¹⁻³⁻⁵⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻⁵⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

or, R¹⁻³⁻⁷ and R¹⁻³⁻⁸ together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻³⁻⁷⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom, sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻⁷⁻²)—;R¹⁻³⁻⁷⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻⁷⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

or, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰ together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻³⁻⁹-1; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom, sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻⁹⁻²)—;R¹⁻³⁻⁹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻⁹⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻¹¹ is independently halogen, hydroxyl, amino, mercapto, cyano,C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻³⁻¹¹-1” R¹⁻³⁻¹¹⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻¹² is independently halogen, hydroxyl, amino, mercapto, cyano,C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻³⁻¹²⁻¹”; R¹⁻³⁻¹²⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁵ is independently hydrogen, —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or “C₁-C₇alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇ heteroaryl optionallysubstituted” by one, two or three R¹⁻⁵⁻⁴;

R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl, C₂-C₇alkenyl, C₂-C₇ alkynyl or C₃-C₁₄ cycloalkyl;

or, R¹⁻⁵⁻¹ and R¹⁻⁵⁻² together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻⁵⁻¹⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom, sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻⁵⁻¹⁻²)—;R¹⁻⁵⁻¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻¹⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁵⁻³ is independently hydrogen, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl orC₁-C₇ heteroaryl;

R¹⁻⁵⁻⁴ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻⁵⁻⁴-1”. R¹⁻⁵⁻⁴⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁶ is independently hydrogen, —CN, —OH or “C₁-C₇ alkyl, C₂-C₇ alkenyl,C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl,or C₁-C₇ heteroaryl” optionally substituted by one, two or three R¹⁻⁶-1;

R¹⁻⁶⁻¹ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻⁶⁻¹⁻¹”; R¹⁻⁶⁻¹⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁷ is independently hydrogen, —OR¹⁻⁷⁻¹, —NR¹⁻⁷⁻²R¹⁻⁷⁻³ or “C₁-C₇alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻⁷⁻⁴;

R¹⁻⁷⁻¹ is independently hydrogen, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl orC₁-C₇ heteroaryl;

R¹⁻⁷⁻² and R¹⁻⁷⁻³ are independently C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇alkynyl or C₃-C₁₄ cycloalkyl;

or, R¹⁻⁷⁻² and R¹⁻⁷⁻³ together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻⁷⁻²⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom, sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻⁷⁻²⁻²)—;R¹⁻⁷⁻²⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁷⁻²⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁷⁻⁴ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻⁷⁻⁴⁻¹”. R¹⁻⁷⁻⁴⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁸ is independently halogen, —OH, amino, mercapto, cyano, C₁-C₇ alkyl,C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or“amino substituted by one or two R¹⁻⁸⁻¹”; R¹⁻⁸⁻¹ is independently C₁-C₇alkyl or C₃-C₁₄ cycloalkyl;

R² is —OR²⁻¹, cyano, carboxyl, or “C₂-C₇ alkyl, C₃-C₁₄ cycloalkyl orC₃-C₁₄ heterocycloalkyl” optionally substituted by one, two or threeR²⁻²;

R²⁻¹ is C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl;

R²⁻² is independently halogen, hydroxyl, amino, C₁-C₇ alkyl, C₁-C₇alkoxy, C₃-C₁₄ cycloalkyl or C₃-C₁₄ heterocycloalkyl;

in any one of the above cases, the heteroatoms in the C₃-C₁₄heterocycloalkyl, C₁-C₇ heteroaryl are independently selected from oneor more of boron, silicon, oxygen, sulfur, selenium, nitrogen andphosphorus; the number of heteroatoms is independently 1, 2, 3 or 4.

In a certain scheme, some substituents in the pyrazolone-fusedpyrimidine compound represented by formula I, the pharmaceuticallyacceptable salt thereof, the solvate thereof, the solvate of thepharmaceutically acceptable salt thereof, the metabolite thereof or theprodrug thereof may further have the following definitions, and thedefinitions of substituents not involved below are as described in anyof the above schemes (hereinafter referred to as “in a certain scheme”):

When A is C₃-C₂₀ cycloalkyl substituted by one or two R¹, the C₃-C₂₀cycloalkyl is for example C₃-C₂₀ monocyclic cycloalkyl, C₃-C₂₀ spirocycloalkyl, C₃-C₂₀ fused cycloalkyl or C₃-C₂₀ bridged cycloalkyl.

The C₃-C₂₀ monocyclic cycloalkyl is for example C₃-C₆ monocycliccycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, for example cyclohexyl.

The C₃-C₂₀ bridged cycloalkyl is for example C₅-C₈ bridged cycloalkyl,for example

In a certain scheme:

When A is C₃-C₂₀ cycloalkyl substituted by one or two R¹, the C₃-C₂₀cycloalkyl is for example C₃-C₂₀ saturated cycloalkyl.

In a certain scheme:

When A is C₃-C₂₀ cycloalkyl substituted by one R¹, the A is for example

The

is for example

for example,

the ratio of

is 1:1”.

The

is for example

for example,

the ratio of

is 1:1”.

In a certain scheme:

When R¹ is independently C₃-C₁₄ heterocycloalkyl, the C₃-C₁₄heterocycloalkyl is for example C₃-C₁₄ monocyclic heterocycloalkyl,C₃-C₁₄ spiro heterocycloalkyl, C₃-C₁₄ fused heterocycloalkyl or C₃-C₁₄bridged heterocycloalkyl.

The C₃-C₁₄ monocyclic heterocycloalkyl is, for example, “C₃-C₉monocyclic heterocycloalkyl having one or two heteroatoms selected fromone or two of N, O and S”, for example, “C₃-C₅ monocyclicheterocycloalkyl having one or two heteroatoms selected from one or twoof N, O and S”, for example, “C₃-C₅ monocyclic heterocycloalkyl havingone or two heteroatoms selected from one or two of N, O and S” and whichis connected to a benzene ring by a nitrogen atom, for example,azetidinyl, morpholinyl, piperidinyl or piperazinyl.

The azetidinyl is for example

The morpholinyl is for example

The piperidinyl is for example or

The piperazinyl is for example H

In a certain scheme:

When R¹ is independently C₃-C₁₄ heterocycloalkyl, the heteroatom of theC₃-C₁₄ heterocycloalkyl may not be substituted.

In a certain scheme:

When R¹ is independently C₃-C₁₄ heterocycloalkyl, the methylene in theC₃-C₁₄ heterocycloalkyl may not be substituted.

In a certain scheme:

When R¹⁻³ and R¹⁻⁴ are independently C₁-C₇ alkyl, the C₁-C₇ alkyl is forexample C₁-C₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl.

In a certain scheme:

When R¹⁻³⁻¹ is independently C₁-C₇ alkyl, the C₁-C₇ alkyl is for exampleC₁-C₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl.

In a certain scheme:

When R¹⁻⁵ is independently C₃-C₁₄ heterocycloalkyl, the C₃-C₁₄heterocycloalkyl is for example C₃-C₁₄ monocyclic heterocycloalkyl,C₃-C₁₄ spiro heterocycloalkyl, C₃-C₁₄ fused heterocycloalkyl or C₃-C₁₄bridged heterocycloalkyl.

The C₃-C₁₄ monocyclic heterocycloalkyl is, for example, “C₃-C₉monocyclic heterocycloalkyl having one or two heteroatoms selected fromone or two of N, O and S”, for example, “C₃-C₅ monocyclicheterocycloalkyl having one or two heteroatoms selected from one or twoof N, O and S”, for example, “C₃-C₅ monocyclic heterocycloalkyl havingone or two heteroatoms selected from one or two of N, O and S” and whichis connected to a benzene ring by a nitrogen atom, for example,azetidinyl.

The azetidinyl is for example

In a certain scheme:

When R¹⁻⁵ is independently C₃-C₁₄ heterocycloalkyl, the heteroatom ofthe C₃-C₁₄ heterocycloalkyl may not be substituted.

In a certain scheme:

When R¹⁻⁵ is independently C₃-C₁₄ heterocycloalkyl, the methylene in theC₃-C₁₄ heterocycloalkyl may not be substituted.

In a certain scheme:

When R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently C₁-C₇ alkyl, the C₁-C₇ alkyl isfor example C₁-C₃ alkyl, for example methyl, ethyl, n-propyl orisopropyl.

In a certain scheme:

When R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently C₃-C₁₄ cycloalkyl, the C₃-C₁₄cycloalkyl is for example C₃-C₁₄ monocyclic cycloalkyl, C₃-C₁₄ spirocycloalkyl, C₃-C₁₄ fused cycloalkyl or C₃-C₁₄ bridged cycloalkyl.

The C₃-C₁₄ monocyclic cycloalkyl is for example C₃-C₆ monocycliccycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, for example cyclobutyl, cyclopentyl or cyclohexyl.

The C₃-C₁₄ bridged cycloalkyl is for example C₅-C₅ bridged cycloalkyl,for example

In a certain scheme:

When R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently C₃-C₁₄ cycloalkyl, the C₃-C₁₄cycloalkyl is for example C₃-C₁₄ saturated cycloalkyl.

In a certain scheme:

When R¹⁻⁵⁻³ is independently C₁-C₇ alkyl, the C₁-C₇ alkyl is for exampleC₁-C₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl.

In a certain scheme:

When R² is C₂-C₇ alkyl optionally substituted by one, two or three R²⁻²,the C₂-C₇ alkyl is for example C₂-C₄ alkyl, for example ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for exampleisopropyl.

In a certain scheme:

When R² is C₂-C₇ alkyl substituted by one R²⁻², R²⁻² is hydroxyl; theC₂-C₇ alkyl substituted by one R²⁻² is for example

In a certain scheme:

When R² is C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R²⁻², the C₃-C₁₄ heterocycloalkyl is for example C₃-C₁₄ monocyclicheterocycloalkyl, C₃-C₁₄ spiro heterocycloalkyl, C₃-C₁₄ fusedheterocycloalkyl or C₃-C₁₄ bridged heterocycloalkyl.

The C₃-C₁₄ monocyclic heterocycloalkyl is, for example, “C₃-C₉monocyclic heterocycloalkyl having one or two heteroatoms selected fromone or two of N, O and S”, for example, “C₃-C₅ monocyclicheterocycloalkyl having one or two heteroatoms selected from one or twoof N, O and S”, for example, “C₃-C₅ monocyclic heterocycloalkyl havingone or two heteroatoms selected from one or two of N, O and S” and whichis connected to a benzene ring by a nitrogen atom, for example,oxetanyl.

The morpholinyl oxetanyl is for example oxetan-3-yl.

In a certain scheme:

When R² is C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R²⁻², the heteroatom of the C₃-C₁₄ heterocycloalkyl may not besubstituted except R²⁻².

In a certain scheme:

When R² is C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R²⁻², the methylene in the C₃-C₁₄ heterocycloalkyl may not besubstituted.

In a certain scheme:

When R² is C₃-C₁₄ heterocycloalkyl substituted by one R²⁻², R²⁻² ishalogen or hydroxyl; the C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²is for example

In a certain scheme:

The ratio of each isomer in the pyrazolone-fused pyrimidine compoundrepresented by formula I may be equal, for example, racemate.

In a certain scheme:

The atoms in the pyrazolone-fused pyrimidine compound represented byformula I, the pharmaceutically acceptable salt thereof, the solvatethereof, the solvate of the pharmaceutically acceptable salt thereof,the metabolite thereof or the prodrug thereof may all exist in theirnatural abundance.

In a certain scheme:

A is

substituted by one or two R¹”.

In a certain scheme:

A is C₃-C₂₀ cycloalkyl substituted by one R¹.

In a certain scheme:

A is

In a certain scheme:

R¹ is independently halogen, —CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, —C(═NR¹⁻⁶)R¹⁻⁷or “C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇heteroaryl” optionally substituted by one, two or three R¹⁻⁸;

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶, —S(═O)₂NR¹⁻³⁻⁷R¹⁻³⁻⁸, —C(═O)NR¹⁻³⁻⁹R¹⁻³⁻¹⁰,or “C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ arylor C₁-C₇ heteroaryl” optionally substituted by one, two or threeR¹⁻³⁻¹¹.

R¹⁻³⁻¹ and R¹⁻³⁻² are independently “C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl or C₆-C₁₀ aryl” optionally substituted by one ortwo R¹⁻³⁻¹⁻¹”; R¹⁻³⁻¹-1 is independently C₁-C₇ alkyl;

R¹⁻³⁻³ is independently hydrogen;

R¹⁻³⁻⁵, R¹⁻³⁻⁶, R¹⁻³⁻⁷, R¹⁻³⁻⁸, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰ are independentlyC₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻¹¹ is independently halogen, hydroxyl, amino, mercapto, cyano,C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻³⁻¹¹-1”; R¹⁻³⁻¹¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁵ is independently hydrogen, —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or “C₁-C₇alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇heteroaryl” optionally substituted by one, two or three R¹⁻⁵⁻⁴;

R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁵-3 is independently hydrogen, C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl;

R¹⁻⁵⁻⁴ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁵⁻⁴⁻¹”; R¹⁻⁵⁻⁴⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁶ is independently hydrogen, —CN, —OH;

R¹⁻⁷ is independently hydrogen, —NR¹⁻⁷⁻²R¹⁻⁷⁻³;

R¹⁻⁷⁻² and R¹⁻⁷⁻³ are independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

or, R¹⁻⁷⁻² and R¹⁻⁷⁻³ together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻⁷⁻²⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom; R¹⁻⁷⁻²⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁸ is independently halogen, —OH, amino, mercapto, cyano, C₁-C₇ alkyl,C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁸⁻¹”; R¹⁻⁸⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl.

In a certain scheme:

R¹ is independently cyano, halogen, —NR¹⁻³R¹⁻⁴, C(═O)R¹⁻⁵,—C(═NR¹⁻⁶)R¹⁻⁷, C₁-C₇ heteroaryl or C₃-C₁₄ heterocycloalkyl.

In a certain scheme:

R¹ is independently —NR¹⁻³R¹⁻⁴, C(═O)R¹⁻⁵ or C₃-C₁₄ heterocycloalkyl.

In a certain scheme:

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹ or C₁-C₇ alkyl;R¹⁻³⁻¹ is independently C₁-C₇ alkyl.

In a certain scheme:

R¹⁻⁵ is independently —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄heterocycloalkyl; R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ is independently hydrogen or C₁-C₇alkyl.

In a certain scheme:

R¹⁻⁵ is independently —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄heterocycloalkyl; R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ is hydrogen.

In a certain scheme:

R² is “C₂-C₇ alkyl, C₃-C₁₄ cycloalkyl or C₃-C₁₄ heterocycloalkyl”optionally substituted by one, two or three R²⁻²;

R²⁻² is independently halogen or hydroxyl.

In a certain scheme:

R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”;R²⁻² is halogen or hydroxyl.

In a certain scheme:

R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”;R²⁻² is hydroxyl.

In a certain scheme:

R² is

In a certain scheme:

A is

substituted by one or two R¹”;

R¹ is independently halogen, —CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, —C(═NR¹⁻⁶)R¹⁻⁷or “C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇heteroaryl” optionally substituted by one, two or three R¹⁻⁸;

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶, —S(═O)₂NR¹⁻³⁻⁷R¹⁻³⁻⁸, —C(═O)NR¹⁻³⁻⁹R¹⁻³⁻¹⁰ or“C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl orC₁-C₇ heteroaryl” optionally substituted by one, two or three R¹⁻³⁻¹¹;

R¹⁻³⁻¹ and R¹⁻³⁻² are independently “C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl or C₆-C₁₀ aryl” optionally substituted by one ortwo R¹⁻³⁻¹⁻¹; R¹⁻³⁻¹⁻¹ is independently C₁-C₇ alkyl;

R¹⁻³⁻³ is independently hydrogen;

R¹⁻³⁻⁵, R¹⁻³⁻⁶, R¹⁻³⁻⁷, R¹⁻³⁻⁸, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰ are independentlyC₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻³⁻¹¹ is independently halogen, hydroxyl, amino, mercapto, cyano,C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻³⁻¹”; R¹⁻³⁻¹¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁵ is independently hydrogen, —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or “C₁-C₇alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇heteroaryl” optionally substituted by one, two or three R¹⁻⁵⁻⁴;

R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁵⁻³ is independently hydrogen, C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl;

R¹⁻⁵⁻⁴ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁵⁻⁴⁻¹”; R¹⁻⁵⁻⁴⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R¹⁻⁶ is independently hydrogen, —CN, —OH;

R¹⁻⁷ is independently hydrogen, —NR¹⁻⁷⁻²R¹⁻⁷⁻³;

R¹⁻⁷⁻² and R¹⁻⁷⁻³ are independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

or, R¹⁻⁷⁻² and R¹⁻⁷⁻³ together with the nitrogen atom they are attachedto form a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻⁷⁻²⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom; R¹⁻⁷⁻²⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;

R¹⁻⁸ is independently halogen, —OH, amino, mercapto, cyano, C₁-C₇ alkyl,C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁸⁻¹”; R¹⁻⁸⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl;

R² is “C₂-C₇ alkyl, C₃-C₁₄ cycloalkyl or C₃-C₁₄ heterocycloalkyl”optionally substituted by one, two or three R²⁻²;

R²⁻² is independently halogen or hydroxyl;

in any one of the above cases, the heteroatoms in the C₃-C₁₄heterocycloalkyl, C₁-C₇ heteroaryl are independently selected from oneor more of boron, silicon, oxygen, sulfur, selenium, nitrogen andphosphorus; the number of heteroatoms is independently 1, 2, 3 or 4.

In a certain scheme:

A is C₃-C₂₀ cycloalkyl substituted by one or two R¹;

R¹ is independently cyano, halogen, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵,—C(═NR¹⁻⁶)R¹⁻⁷, C₁-C₇ heteroaryl or C₃-C₁₄ heterocycloalkyl;

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹ or C₁-C₇ alkyl;R¹⁻³⁻¹ is independently C₁-C₇ alkyl;

R¹⁻⁵ is independently —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄heterocycloalkyl; R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ is independently hydrogen or C₁-C₇alkyl;

R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”;R²⁻² is halogen or hydroxyl.

In a certain scheme:

A is C₃-C₂₀ cycloalkyl substituted by one R¹;

R¹ is —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵ or C₃-C₁₄ heterocycloalkyl;

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹ or C₁-C₇ alkyl;R¹⁻³⁻¹ is independently C₁-C₇ alkyl;

R¹⁻⁵ is —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄ heterocycloalkyl; R¹⁻⁵⁻¹ andR¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;R¹⁻⁵⁻³ is hydrogen or C₁-C₇ alkyl;

R² is C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²;R²⁻² is hydroxyl.

In a certain scheme:

A is C₃-C₂₀ cycloalkyl substituted by one R¹;

R¹ is —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵ or C₃-C₁₄ heterocycloalkyl;

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹ or C₁-C₇ alkyl;R¹⁻³⁻¹ is independently C₁-C₇ alkyl;

R¹⁻⁵ is —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄ heterocycloalkyl; R¹⁻⁵⁻¹ andR¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;R¹⁻⁵⁻³ is hydrogen;

R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”;R²⁻² is hydroxyl.

In a certain scheme:

A is

R¹ is —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵ or C₃-C₁₄ heterocycloalkyl;

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹ or C₁-C₇ alkyl;R¹⁻³⁻¹ is independently C₁-C₇ alkyl;

R¹⁻⁵ is —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄ heterocycloalkyl; R¹⁻⁵⁻¹ andR¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;R¹⁻⁵⁻³ is hydrogen or C₁-C₇ alkyl;

R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”;R²⁻² is hydroxyl.

In a certain scheme:

A is

R¹ is —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵ or C₃-C₁₄ heterocycloalkyl;

R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹ or C₁-C₇ alkyl;R¹⁻³⁻¹ is independently C₁-C₇ alkyl;

R¹⁻⁵ is —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄ heterocycloalkyl; R¹⁻⁵⁻¹ andR¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;R¹⁻⁵⁻³ is hydrogen or C₁-C₇ alkyl;

R² is

In a certain scheme, in the pyrazolone-fused pyrimidine compoundrepresented by formula II, the pharmaceutically acceptable salt thereof,the solvate thereof, the solvate of the pharmaceutically acceptable saltthereof, the metabolite thereof or the prodrug thereof, thepyrazolone-fused pyrimidine compound represented by formula II is any ofthe following compounds:

In a certain scheme, in the pyrazolone-fused pyrimidine compoundrepresented by formula II, the pharmaceutically acceptable salt thereof,the solvate thereof, the solvate of the pharmaceutically acceptable saltthereof, the metabolite thereof or the prodrug thereof, thepyrazolone-fused pyrimidine compound represented by formula II is any ofthe following compounds:

its ¹H NMR (400 MHz, MeOD) is δ 8.85 (s, 1H), 8.00 (t, J=7.9 Hz, 1H),7.80 (d, J=8.1 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.62 (d, J=8.6 Hz, 2H),7.28 (d, J=8.6 Hz, 2H), 5.78-5.68 (m, 1H), 5.06 (d, J=10.3 Hz, 1H), 4.95(s, 1H), 4.82 (s, 2H), 3.82-3.76 (m, 1H), 2.81 (s, 1H), 2.71 (s, 3H),2.49 (s, 1H), 2.08 (d, J=10.9 Hz, 3H), 1.94 (d, J=15.0 Hz, 3H), 1.72 (s,4H), 1.59 (d, J=7.0 Hz, 6H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.87 (d, J=2.1 Hz, 1H), 7.91 (td,J=7.9, 1.5 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.54 (t, J=7.9 Hz, 2H), 7.39(d, J=7.7 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 5.72 (ddt, J=16.4, 10.2, 6.2Hz, 1H), 5.07 (dd, J=10.2, 1.1 Hz, 1H), 4.96 (dd, J=17.1, 1.2 Hz, 1H),4.77 (d, J=6.2 Hz, 2H), 4.25-4.10 (m, 2H), 3.95 (s, 1H), 2.73 (s, 1H),2.56 (dt, J=15.5, 10.8 Hz, 1H), 2.28 (d, J=7.9 Hz, 1H), 2.14 (d, J=10.6Hz, 1H), 2.05-1.97 (m, 1H), 1.78 (dd, J=19.0, 8.5 Hz, 1H), 1.67 (dt,J=10.1, 6.1 Hz, 3H), 1.61 (s, 6H), 1.59-1.44 (m, 1H), 1.34-1.26 (m, 3H);

its ¹H NMR (400 MHz, MeOD) is δ 8.84 (d, J=1.4 Hz, 1H), 8.00 (td, J=7.9,4.0 Hz, 1H), 7.83-7.76 (m, 1H), 7.67 (dd, J=7.7, 0.7 Hz, 1H), 7.60 (dd,J=8.4, 5.7 Hz, 2H), 7.19 (dd, J=13.2, 8.6 Hz, 2H), 5.73 (ddd, J=17.0,6.1, 4.1 Hz, 1H), 5.08-5.03 (m, 1H), 4.95 (d, J=1.3 Hz, 1H), 4.86-4.79(m, 2H), 2.72 (s, 1H), 2.58 (s, 1H), 2.27 (d, J=6.7 Hz, 1H), 2.13 (d,J=10.0 Hz, 1H), 1.96 (d, J=10.2 Hz, 1H), 1.80-1.66 (m, 4H), 1.64-1.52(m, 7H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.86 (d, J=4.2 Hz, 1H), 7.97-7.88 (m,1H), 7.79 (d, J=8.0 Hz, 1H), 7.53 (dd, J=12.3, 8.5 Hz, 2H), 7.39 (d,J=7.6 Hz, 1H), 7.28-7.15 (m, 2H), 5.80-5.65 (m, 1H), 5.06 (d, J=10.0 Hz,1H), 4.95 (d, J=17.1 Hz, 1H), 4.77 (d, J=6.0 Hz, 2H), 3.10 (d, J=12.1Hz, 3H), 2.98 (s, 3H), 2.67-2.57 (m, 1H), 2.14 (dd, J=20.9, 10.3 Hz,1H), 2.06-1.97 (m, 2H), 1.92 (d, J=14.0 Hz, 1H), 1.78-1.66 (m, 4H), 1.61(s, 6H), 1.49 (dd, J=22.8, 12.2 Hz, 1H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.85 (d, J=4.7 Hz, 1H), 7.91 (dt,J=10.7, 7.9 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.53 (dd, J=12.0, 8.5 Hz,2H), 7.39 (dd, J=7.6, 2.4 Hz, 1H), 7.22 (dd, J=19.5, 8.5 Hz, 2H), 5.71(ddt, J=16.4, 10.2, 6.2 Hz, 1H), 5.06 (d, J=10.2 Hz, 1H), 4.95 (d,J=17.1 Hz, 1H), 4.77 (d, J=6.1 Hz, 2H), 4.21 (dd, J=16.4, 8.6 Hz, 2H),4.10-4.02 (m, 2H), 2.63-2.52 (m, 2H), 2.35-2.20 (m, 2H), 2.15-2.07 (m,1H), 2.00 (dd, J=13.4, 3.0 Hz, 2H), 1.92-1.83 (m, 1H), 1.79-1.63 (m,4H), 1.60 (s, 6H), 1.48 (ddd, J=24.7, 12.5, 2.5 Hz, 1H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.86 (s, 1H), 7.93-7.85 (m, 1H), 7.78(d, J=7.8 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.39 (dd, J=7.6, 0.7 Hz, 1H),7.19 (d, J=8.5 Hz, 2H), 5.71 (ddt, J=16.4, 10.2, 6.2 Hz, 1H), 5.05 (dd,J=10.2, 1.1 Hz, 1H), 4.94 (dd, J=17.1, 1.3 Hz, 1H), 4.77 (d, J=6.2 Hz,2H), 4.11 (d, J=8.9 Hz, 1H), 3.24 (t, J=7.0 Hz, 4H), 2.52-2.43 (m, 1H),2.14-2.00 (m, 3H), 1.92 (d, J=11.2 Hz, 4H), 1.60 (s, 6H), 1.45 (dt,J=14.9, 7.5 Hz, 2H), 1.23-1.08 (m, 2H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.84 (d, J=3.7 Hz, 1H), 7.94 (dd,J=14.8, 6.9 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.58-7.50 (m, 2H), 7.42(dd, J=7.5, 4.1 Hz, 1H), 7.22 (dd, J=15.8, 8.5 Hz, 2H), 5.71 (dd,J=11.5, 5.4 Hz, 2H), 5.07 (d, J=10.2 Hz, 1H), 4.95 (d, J=17.1 Hz, 1H),4.77 (d, J=6.1 Hz, 2H), 2.82-2.72 (m, 1H), 2.60 (s, 1H), 2.12-2.01 (m,3H), 1.92 (d, J=12.5 Hz, 1H), 1.81-1.67 (m, 3H), 1.62 (s, 6H), 1.54-1.43(m, 1H), 0.93-0.78 (m, 3H), 0.52 (s, 2H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.88 (s, 1H), 7.91 (t, J=7.9 Hz, 1H),7.77 (d, J=7.9 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.40 (d, J=7.4 Hz, 1H),7.19 (d, J=8.5 Hz, 2H), 5.78-5.66 (m, 1H), 5.07 (dd, J=10.2, 1.0 Hz,1H), 4.96 (dd, J=17.1, 1.2 Hz, 1H), 4.77 (d, J=6.2 Hz, 2H), 4.42 (d,J=7.6 Hz, 1H), 3.49-3.35 (m, 1H), 3.04 (s, 3H), 2.57-2.46 (m, 1H),2.29-2.17 (m, 2H), 2.05-1.96 (m, 8H), 1.56-1.65 (m, 2H), 1.41-1.50 (m,2H);

its ¹H NMR (400 MHz, MeOD) is δ 8.84 (s, 1H), 8.02 (m, 1H), 7.80 (m,1H), 7.72-7.58 (m, 3H), 7.25 (m, 2H), 5.73 (ddt, J=16.5, 10.3, 6.1 Hz,1H), 5.05 (dd, J=10.2, 1.0 Hz, 1H), 4.95 (d, 1H), 4.83 (d, J=6.1 Hz,2H), 3.54-3.42 (m, 1H), 2.59 (m, 1H), 2.14 (m, 1H), 1.98 (m, 2H), 1.83(m, 1H), 1.68 (m, 2H), 1.60 (s, 6H), 1.50 (m, 2H);

its ¹H NMR (400 MHz, DMSO) is δ 10.28 (s, 1H), 8.88 (d, J=1.8 Hz, 1H),8.09-7.97 (m, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.66 (dd, J=20.6, 8.5 Hz,3H), 7.19 (dd, J=11.1, 8.7 Hz, 2H), 5.74-5.61 (m, 1H), 5.00 (d, J=10.2Hz, 1H), 4.82 (d, J=17.1 Hz, 1H), 4.69 (d, J=5.5 Hz, 2H), 3.23 (s, 1H),2.74 (t, J=12.1 Hz, 1H), 2.53 (s, 1H), 2.12 (d, J=10.1 Hz, 1H), 1.98 (d,J=13.2 Hz, 1H), 1.82 (d, J=13.2 Hz, 2H), 1.77-1.57 (m, 3H), 1.49 (d,J=18.2 Hz, 6H);

its ¹H NMR (400 MHz, DMSO) is δ 10.27 (s, 1H), 8.89 (s, 1H), 8.12 (s,1H), 7.74 (dd, J=22.6, 8.3 Hz, 3H), 7.64 (d, J=7.3 Hz, 1H), 7.37 (d,J=8.5 Hz, 2H), 5.76-5.61 (m, 1H), 5.34 (s, 1H), 5.01 (dd, J=10.3, 1.2Hz, 1H), 4.84 (d, J=17.1 Hz, 1H), 4.70 (d, J=5.7 Hz, 2H), 3.62 (s, 1H),3.12 (s, 1H), 2.71-2.58 (m, 8H), 2.38 (d, J=9.2 Hz, 2H), 1.47 (s, 6H),1.32-1.24 (m, 1H);

its ¹H NMR (400 MHz, DMSO) is δ 10.26 (s, 1H), 8.88 (s, 1H), 8.07 (t,J=7.8 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.65 (dd, J=14.5, 7.9 Hz, 2H),7.22 (d, J=8.5 Hz, 2H), 5.74-5.60 (m, 1H), 5.35 (s, 1H), 5.00 (d, J=10.3Hz, 1H), 4.83 (d, J=17.1 Hz, 1H), 4.69 (d, J=5.6 Hz, 2H), 3.74 (s, 3H),3.24-3.15 (m, 1H), 2.77 (t, J=12.0 Hz, 1H), 2.37 (d, J=14.0 Hz, 1H),2.25 (td, J=13.4, 4.6 Hz, 1H), 1.99-1.84 (m, 3H), 1.67-1.50 (m, 2H),1.49 (d, J=14.0 Hz, 6H);

its ¹H NMR (400 MHz, MeOD) is δ 8.86 (s, 0H), 8.11-8.01 (m, 1H), 7.94(d, J=7.9 Hz, 2H), 7.67 (d, J=7.6 Hz, 2H), 7.62 (d, J=8.6 Hz, 2H), 7.28(d, J=8.5 Hz, 2H), 5.83-5.74 (m, 1H), 5.09 (dd, J=7.9, 4.4 Hz, 3H), 4.98(dd, J=17.1, 1.3 Hz, 2H), 4.85 (d, J=6.7 Hz, 2H), 2.87 (s, 1H), 2.64 (s,1H), 2.47 (s, 3H), 1.97-1.67 (m, 8H);

its ¹H NMR (400 MHz, MeOD) is δ 8.87 (d, J=6.6 Hz, 1H), 8.06 (t, J=7.9Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.68 (dd, J=7.8, 5.4 Hz, 2H), 7.61 (d,J=8.6 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.24 (t, J=8.7 Hz, 1H), 5.84-5.72(m, 1H), 5.09 (d, J=6.2 Hz, 2H), 5.07 (d, J=1.3 Hz, 1H), 5.02-4.94 (m,2H), 4.90 (s, 2H), 4.84 (d, J=6.7 Hz, 2H), 3.15 (d, J=2.6 Hz, 1H), 3.08(s, 1H), 2.95 (s, 1H), 2.71 (s, 1H), 2.43 (s, 1H), 1.93-2.03 (m, 3H),1.76 (s, 2H), 1.51 (s, 1H), 1.31 (d, J=4.3 Hz, 3H), 0.89 (dd, J=20.1,9.0 Hz, 4H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.87-8.79 (m, 1H), 8.14-8.07 (m, 1H),8.04-7.96 (m, 1H), 7.89-7.80 (m, 1H), 7.61-7.50 (m, 2H), 7.38-7.32 (m,1H), 7.25-7.19 (m, 1H), 7.01 (t, J=3.4 Hz, 1H), 5.72 (ddd, J=16.6, 11.1,8.6 Hz, 1H), 5.17-5.09 (m, 2H), 5.04-4.98 (m, 1H), 4.98-4.92 (m, 1H),4.87-4.77 (m, 2H), 4.73-4.64 (m, 2H), 4.20-4.06 (m, 1H), 3.47-3.38 (m,1H), 3.38-3.29 (m, 1H), 3.05-2.98 (m, 1H), 2.49-2.35 (m, 2H), 2.27-2.17(m, 1H), 2.07-1.86 (m, 4H), 1.75-1.60 (m, 3H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.77 (s, 1H), 8.16-8.07 (m, 1H), 8.03(d, J=7.6 Hz, 1H), 7.83-7.75 (m, 1H), 7.56 (dd, J=12.6, 6.1 Hz, 2H),7.33 (d, J=8.5 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 5.72 (dd, J=17.0, 10.3Hz, 1H), 5.13 (dd, J=9.1, 6.1 Hz, 2H), 4.96 (d, J=17.0 Hz, 2H), 4.81 (d,J=7.2 Hz, 2H), 4.69 (d, J=6.2 Hz, 2H), 4.41-4.28 (m, 2H), 3.86 (s, 1H),3.77 (t, J=6.6 Hz, 1H), 3.63-3.50 (m, 2H), 2.98 (m, 1H), 2.15 (m, 1H),1.97 (dd, J=18.9, 9.6 Hz, 2H), 1.78 (d, J=5.0 Hz, 2H), 1.65 (d, J=8.7Hz, 2H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.69 (s, 1H), 8.18 (d, J=8.0 Hz, 1H),8.10 (dd, J=17.9, 7.6 Hz, 1H), 7.81-7.72 (m, 1H), 7.63-7.49 (m, 2H),7.25 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 5.70 (d, J=6.8 Hz, 1H),5.15 (d, J=10.1 Hz, 1H), 5.14-5.07 (m, 1H), 4.95 (d, J=16.6 Hz, 1H),4.83 (t, J=6.7 Hz, 2H), 4.71 (s, 2H), 2.54 (dd, J=24.9, 12.6 Hz, 2H),2.30 (d, J=11.2 Hz, 1H), 2.18 (d, J=13.5 Hz, 1H), 2.02 (d, J=12.9 Hz,1H), 1.96-1.80 (m, 2H), 1.78 (d, J=16.1 Hz, 1H), 1.49 (dd, J=26.4, 11.2Hz, 2H);

its ¹H NMR (400 MHz, Methanol-d₄) is δ 8.85 (d, J=1.1 Hz, 1H), 8.05 (td,J=7.9, 4.8 Hz, 1H), 7.96-7.86 (m, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.59(ddd, J=9.2, 4.6, 2.3 Hz, 2H), 7.25-7.19 (m, 1H), 7.19-7.11 (m, 1H),5.78 (ddt, J=16.5, 10.1, 6.1 Hz, 1H), 5.12-5.07 (m, 2H), 5.06 (t, J=1.3Hz, 1H), 4.98 (dd, J=17.0, 1.4 Hz, 1H), 4.90 (d, J=1.4 Hz, 2H),4.25-4.19 (m, 1H), 4.14 (dd, J=14.1, 7.1 Hz, 1H), 2.34-2.12 (m, 2H),2.07 (dd, J=17.0, 4.1 Hz, 1H), 1.99-1.82 (m, 1H), 1.74-1.65 (m, 2H),1.65-1.53 (m, 2H), 1.31 (d, J=4.2 Hz, 3H), 1.29-1.25 (m, 2H);

its ¹H NMR (400 MHz, Methanol-d₄) is δ 8.84 (s, 1H), 8.05 (t, J=7.9 Hz,1H), 7.92 (d, J=8.1 Hz, 1H), 7.66 (dd, J=7.6, 0.9 Hz, 1H), 7.63-7.53 (m,2H), 7.22-7.14 (m, 2H), 5.84-5.74 (m, 1H), 5.10-5.07 (m, 2H), 5.06 (q,J=1.3 Hz, 1H), 4.98 (dq, J=17.0, 1.4 Hz, 1H), 4.89 (dt, J=6.1, 1.4 Hz,2H), 2.71 (d, J=6.9 Hz, 1H), 2.59 (s, 1H), 2.24 (dd, J=16.4, 7.8 Hz,2H), 2.04 (d, J=8.5 Hz, 1H), 1.73 (td, J=10.9, 6.8 Hz, 6H).

In a certain scheme, in the pyrazolone-fused pyrimidine compoundrepresented by formula II, the pharmaceutically acceptable salt thereof,the solvate thereof, the solvate of the pharmaceutically acceptable saltthereof, the metabolite thereof or the prodrug thereof, thepyrazolone-fused pyrimidine compound represented by formula II is any ofthe following compounds:

In a certain scheme, in the pyrazolone-fused pyrimidine compoundrepresented by formula II, the pharmaceutically acceptable salt thereof,the solvate thereof, the solvate of the pharmaceutically acceptable saltthereof, the metabolite thereof or the prodrug thereof, thepyrazolone-fused pyrimidine compound represented by formula II is any ofthe following compounds:

(I-1-1), its ¹H NMR (400 MHz, MeOD) is δ 8.85 (s, 1H), 8.46 (s, 2H),7.99 (t, J=7.9 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.65 (dd, J=16.6, 8.1Hz, 3H), 7.22 (d, J=8.6 Hz, 2H), 5.73 (ddt, J=16.3, 10.2, 6.1 Hz, 1H),5.05 (dd, J=10.3, 1.1 Hz, 1H), 4.93 (dd, J=17.1, 1.3 Hz, 1H), 4.82 (d,J=6.1 Hz, 2H), 2.90 (s, 6H), 2.60 (d, J=8.4 Hz, 1H), 2.21 (s, 2H), 2.10(d, J=10.6 Hz, 2H), 1.70 (d, J=11.4 Hz, 4H), 1.59 (s, 6H);

(I-1-2), its ¹H NMR (400 MHz, CDCl₃) is δ 8.86 (s, 1H), 8.54 (s, 1H),7.95 (t, J=7.9 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H),7.43 (d, J=7.6 Hz, 1H), 7.32 (d, J=8.5 Hz, 2H), 5.72 (ddt, J=16.5, 10.3,6.2 Hz, 1H), 5.06 (d, J=10.2 Hz, 1H), 4.95 (dd, J=17.1, 1.0 Hz, 1H),4.75 (d, J=6.1 Hz, 2H), 3.05 (m, 1H), 2.93 (m, 1H), 2.68 (s, 6H), 2.32(m, 2H), 1.84 (m, 6H), 1.60 (s, 6H);

(I-3-1), its ¹H NMR (400 MHz, CDCl₃) is δ 8.87 (s, 1H), 7.90 (t, J=7.9Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.39 (dd,J=7.6, 0.5 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 5.72 (ddt, J=16.4, 10.2, 6.2Hz, 1H), 5.06 (dd, J=10.2, 1.0 Hz, 1H), 4.95 (dd, J=17.1, 1.2 Hz, 1H),4.76 (d, J=6.2 Hz, 2H), 4.04 (s, 1H), 2.66 (m, 4H), 2.58-2.47 (m, 1H),2.16 (m, 4H), 1.96 (m, 2H), 1.87-1.78 (m, 4H), 1.60 (s, 6H), 1.58-1.39(m, 4H);

(I-3-2), its ¹H NMR (400 MHz, CDCl₃) is δ 8.87 (s, 1H), 7.92 (t, J=7.9Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.38 (d, J=7.6Hz, 1H), 7.29 (t, J=4.2 Hz, 2H), 5.79-5.66 (m, 1H), 5.06 (dd, J=10.2,1.0 Hz, 1H), 4.96 (dd, J=17.1, 1.2 Hz, 1H), 4.77 (d, J=6.2 Hz, 2H), 4.02(s, 1H), 2.70-2.50 (m, 5H), 2.26 (s, 1H), 1.98 (m, 4H), 1.82 (s, 4H),1.69-1.56 (m, 10H);

(I-8-1), its ¹H NMR (400 MHz, CDCl₃) is δ 8.86 (s, 1H), 7.93-7.85 (m,1H), 7.78 (d, J=7.8 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.39 (dd, J=7.6,0.7 Hz, 1H), 7.19 (d, J=8.5 Hz, 2H), 5.71 (ddt, J=16.4, 10.2, 6.2 Hz,1H), 5.05 (dd, J=10.2, 1.1 Hz, 1H), 4.94 (dd, J=17.1, 1.3 Hz, 1H), 4.77(d, J=6.2 Hz, 2H), 4.11 (d, J=8.9 Hz, 1H), 3.24 (t, J=7.0 Hz, 4H),2.52-2.43 (m, 1H), 2.14-2.00 (m, 3H), 1.92 (d, J=11.2 Hz, 4H), 1.60 (s,6H), 1.45 (dt, J=14.9, 7.5 Hz, 2H), 1.23-1.08 (m, 2H);

(I-8-2), its ¹H NMR (400 MHz, CDCl₃) is δ8.87 (s, 1H), 7.92 (d, J=7.8Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.39 (d, J=7.6Hz, 1H), 7.29-7.25 (m, 2H), 5.82-5.63 (m, 1H), 5.12-4.91 (m, 2H), 4.78(d, J=6.2 Hz, 2H), 4.01 (s, 1H), 3.17 (s, 4H), 2.53 (s, 1H), 2.33 (s,1H), 2.06 (d, J=4.4 Hz, 2H), 1.89 (d, J=11.6 Hz, 2H), 1.75 (d, J=14.1Hz, 2H), 1.59 (d, J=17.2 Hz, 8H), 1.46 (t, J=13.1 Hz, 2H);

(I-15-1), its ¹H NMR (400 MHz, MeOD) is δ 8.84 (s, 1H), 8.04 (t, J=7.9Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.60 (d, J=8.6Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 5.78 (ddt, J=16.3, 10.3, 6.1 Hz, 1H),5.12-5.05 (m, 3H), 4.98 (dd, J=17.1, 1.3 Hz, 1H), 4.89 (d, J=6.1 Hz,2H), 4.84 (s, 2H), 3.68 (s, 2H), 2.97-2.86 (m, 1H), 2.66 (s, 6H),2.60-2.50 (m, 1H), 2.15 (d, J=8.6 Hz, 2H), 2.04 (d, J=9.0 Hz, 2H),1.66-1.54 (m, 4H);

(I-15-2), its ¹H NMR (400 MHz, MeOD) is δ 8.83 (s, 1H), 8.04 (t, J=7.9Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.67-7.62 (m, 1H), 7.59 (d, J=8.6 Hz,2H), 7.29 (d, J=8.5 Hz, 2H), 5.76 (ddt, J=16.3, 10.2, 6.1 Hz, 1H),5.10-5.02 (m, 3H), 4.96 (dd, J=17.1, 1.3 Hz, 1H), 4.87 (d, J=6.8 Hz,2H), 4.82 (d, J=6.8 Hz, 2H), 2.73 (d, J=4.2 Hz, 1H), 2.29 (d, J=21.9 Hz,7H), 2.04-1.90 (m, 4H), 1.66 (dd, J=15.6, 6.1 Hz, 4H);

(I-36-1), its ¹H NMR (400 MHz, CDCl₃) is δ 8.88 (d, J=2.6 Hz, 1H), 8.09(dd, J=15.0, 7.8 Hz, 1H), 7.99-7.83 (m, 2H), 7.54 (t, J=9.5 Hz, 2H),7.39 (d, J=8.7 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 5.74 (dq, J=10.5, 5.9Hz, 1H), 5.12 (t, J=8.8 Hz, 3H), 4.99 (d, J=17.1 Hz, 1H), 4.80 (d, J=6.3Hz, 2H), 4.67 (d, J=6.0 Hz, 2H), 3.39-3.24 (m, 4H), 2.60-2.34 (m, 3H),2.14 (dt, J=14.0, 6.8 Hz, 3H), 1.96 (d, J=10.8 Hz, 4H), 1.55-1.37 (m,2H), 1.27-1.12 (m, 2H);

(I-36-2), its ¹H NMR (400 MHz, MeOD) is δ 8.86 (s, 1H), 8.02 (dt,J=24.0, 7.9 Hz, 3H), 7.64 (dd, J=27.1, 8.1 Hz, 3H), 7.27 (t, J=8.6 Hz,2H), 7.01-6.91 (m, 3H), 6.72-6.64 (m, 3H), 5.79 (ddd, J=16.3, 11.2, 6.1Hz, 1H), 5.10-5.05 (m, 2H), 4.85 (d, J=6.8 Hz, 2H), 2.57 (d, J=10.7 Hz,1H), 2.48-2.28 (m, 3H), 2.23-2.06 (m, 3H), 1.98-1.71 (m, 6H), 1.58 (dd,J=23.2, 12.9 Hz, 3H), 1.44 (ddd, J=16.1, 13.2, 3.5 Hz, 2H), 1.19-1.00(m, 2H);

(I-41-1), its ¹H NMR (400 MHz, Chloroform-d) is δ 9.00 (s, 1H), 8.30 (d,J=8.6 Hz, 1H), 8.22 (d, J=2.4 Hz, 1H), 7.96 (t, J=7.9 Hz, 1H), 7.73 (dd,J=8.1, 0.8 Hz, 1H), 7.55 (dd, J=8.7, 2.4 Hz, 1H), 7.44 (dd, J=7.7, 0.8Hz, 1H), 5.77-5.66 (m, 1H), 5.12-5.05 (m, 1H), 4.97 (dq, J=17.0, 1.4 Hz,1H), 4.76 (dt, J=6.3, 1.3 Hz, 2H), 2.70 (s, 1H), 2.56 (s, 6H), 2.23 (q,J=9.5 Hz, 4H), 2.11-2.01 (m, 4H), 1.58 (t, J=10.3 Hz, 6H);

(I-41-2), its ¹H NMR (400 MHz, Chloroform-d) is δ8.99 (s, 1H), 8.54 (s,1H), 8.32 (d, J=8.7 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.10 (t, J=7.7 Hz,1H), 7.92 (s, 1H), 7.78 (dd, J=8.1, 0.8 Hz, 1H), 7.47-7.41 (m, 1H),5.79-5.71 (m, 1H), 5.08 (dq, J=10.1, 1.2 Hz, 1H), 4.97 (dq, J=17.0, 1.3Hz, 1H), 4.77 (dt, J=6.2, 1.4 Hz, 2H), 3.99 (s, 1H), 2.75 (d, J=11.0 Hz,1H), 2.52 (s, 6H), 2.32-2.18 (m, 1H), 2.09 (d, J=14.4 Hz, 4H), 1.31 (d,J=22.8 Hz, 4H);

wherein,

means that the cis-trans conformation is uncertain.

In a certain scheme, in the pyrazolone-fused pyrimidine compoundrepresented by formula II, the pharmaceutically acceptable salt thereof,the solvate thereof, the solvate of the pharmaceutically acceptable saltthereof, the metabolite thereof or the prodrug thereof, thepyrazolone-fused pyrimidine compound represented by formula II is any ofthe following compounds:

(I-8-1), its ¹H NMR (400 MHz, CDCl₃) has a peak of 1.23-1.08;

wherein,

means that the cis-trans conformation is uncertain.

In a certain scheme, in the pyrazolone-fused pyrimidine compoundrepresented by formula II, the pharmaceutically acceptable salt thereof,the solvate thereof, the solvate of the pharmaceutically acceptable saltthereof, the metabolite thereof or the prodrug thereof, thepyrazolone-fused pyrimidine compound represented by formula II is any ofthe following compounds:

(I-1-1) with a retention time of 10.55 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→50% mobile phase B;

(I-1-2) with a retention time of 10.78 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1 % formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→50% mobile phase B;

(I-3-1) with a retention time of 11.01 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonilrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→50% mobile phase B;

(I-3-2) with a retention time of 11.20 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→50% mobile phase B;

(I-8-1) with a retention time of 10.78 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→50% mobile phase B;

(I-8-2) with a retention time of 11.00 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→50% mobile phase B;

(I-15-1) with a retention time of 7.02 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→95% mobile phase B;

(I-15-2) with a retention time of 7.16 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→95% mobile phase B;

(I-36-1) with a retention time of 7.14 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→95% mobile phase B;

(I-36-2) with a retention time of 7.15 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→95% mobile phase B;

(I-41-1) with a retention time of 6.17 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→95% mobile phase B;

(I-41-2) with a retention time of 6.28 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→95% mobile phase B;

wherein,

means that the cis-trans conformation is uncertain.

In a certain scheme, in the pyrazolone-fused pyrimidine compoundrepresented by formula II, the pharmaceutically acceptable salt thereof,the solvate thereof, the solvate of the pharmaceutically acceptable saltthereof, the metabolite thereof or the prodrug thereof, thepyrazolone-fused pyrimidine compound represented by formula II is any ofthe following compounds:

The present disclosure also provides a preparation method of thecompound II, the method is any of the following methods:

method 1, comprising the following steps: step I, oxidizing compoundII-1A by an oxidant in an organic solvent to obtain compound II-1B; stepII, reacting compound II-1B with compound II-1C in an organic solventand under alkaline conditions to obtain compound II;

method 2, comprising the following steps: step I, hydrolyzing compoundII-2A (R¹ is —(C═O)—O—C₂H₅) to obtain compound II-2B (R¹ is —(C═O)—OH);step II, a condensation reaction is carried out between compound II-2Band an amino compound in an organic solvent to obtain compound II (R¹ is—(C═O)—NR¹⁻⁵⁻¹R¹⁻⁵⁻²).

The conditions and steps of the reaction described in method 1 may beconventional conditions and steps in the art. The following reactionconditions are particularly preferred in the present disclosure:

Step 1, the organic solvent is preferably one or more of methanol,dichloromethane, acetonitrile, toluene and DMF, more preferablydichloromethane or toluene; the oxidant may be an oxidant commonly usedin the art to oxidize thioether to sulfoxide, preferablym-chloroperoxybenzoic acid (m-CPBA); the molar ratio of compound II-1Ato m-CPBA is preferably 1: (1-1.2), the reaction time is preferably 1-12hours, and the reaction temperature is preferably 0° C.-35° C.

Step 2, the organic solvent is preferably dichloromethane or toluene;the alkaline condition is preferably an organic base such asN,N-diisopropylethylamine (DIPEA) or triethylamine, more preferablyN,N-diisopropylethylamine (DIPEA); the molar ratio of compound II-1B,compound II-1C and DIPEA is preferably 1:1:2, the reaction time ispreferably 0-12 hours, and the reaction temperature is preferably 0°C.-35° C.

The conditions and steps of the reaction described in method 2 may beconventional conditions and steps in the art. The following reactionconditions are particularly preferred in the present disclosure:

Step I, the hydrolysis reaction conditions are any suitable reactionconditions commonly used in the art, such as alkaline hydrolysis or acidhydrolysis, and alkaline hydrolysis is for example sodium hydroxidehydrolysis or lithium hydroxide hydrolysis.

Step II, the amino compound may be a primary or secondary amine; theorganic solvent is preferably dichloromethane or DMF; the condensationreaction is carried out under any suitable reaction conditions commonlyused in the art, such as EDCI/HOBT/DIPEA or HATU/DIPEA.

The present disclosure also provides a compound represented by formulaII-1C:

wherein, X is CH or N, A is defined as above.

In a certain scheme, the compound represented by formula II-1C may beany of the following compounds:

In a certain scheme, the compound represented by formula II-1C may beany of the following compounds:

its ¹H NMR (400 MHz, CDCl₃) is δ 7.08-6.96 (m, 2H), 6.70-6.60 (m, 2H),3.57 (s, 2H), 3.22 (t, J=7.0 Hz, 4H), 2.38 (tt, J=12.1, 3.2 Hz, 1H),2.15-1.95 (m, 5H), 1.95-1.81 (m, 4H), 1.51-1.30 (m, 2H), 1.21-1.04 (m,2H);

or,

its ¹H NMR (400 MHz, MeOD) is δ 7.10-6.97 (m, 2H), 6.74-6.63 (m, 2H),4.22-4.08 (t, J=8.0 Hz, 4H), 3.47-3.38 (m, 1H), 2.61-2.52 (m, 1H),2.52-2.28 (m, 2H), 1.92-1.62 (m, 8H).

The present disclosure also provides a preparation method of thecompound represented by formula II-1C, the method is any of thefollowing methods:

method A: step I, protecting amino N of compound II-1C1 in an organicsolvent under alkaline condition to obtain compound II-1C2; step II, aSuzuki reaction is carried out between compound II-1C2 and compoundII-1C3 to obtain compound II-1C4; step III, removing the ketal ofcompound II-1C4 to obtain compound II-1C5; step IV, a reductiveamination reaction is carried out with compound II-1C5 to obtaincompound II-1C6; step V, removing the amino protecting group PG with areducing agent and reducting the double bond simultaneously to obtaincompound II-1C;

wherein, PG is an amino protecting group, R¹ is —NR¹⁻³R¹⁻⁴, and R¹⁻³ andR¹⁻⁴ are defined as above;

method B, comprising the following steps: step I, a Suzuki reaction iscarried out between compound II-1C′ and compound II-1C2′ to obtaincompound II-1C3′; step II, a reduction reaction is carried out withcompound II-1C3′ to obtain compound II-1C;

wherein, R¹ is —C(═O)R¹⁻⁵, R¹⁻⁵ is defined as above;

method C, comprising the following steps: step I, a reductive aminationreaction is carried out with compound II-1C1″ (ring A is oxo-C₄-C₆cycloalkyl) to obtain compound II-1C2″ (R¹ is —NR¹⁻³R¹⁻⁴); step II, aBuchwald reaction is carried out between compound II-1C2″ andbenzophenone imine to obtain compound II-1C3″ (R¹ is —NR¹⁻³R¹⁻⁴); stepIII, removing the diphenyl of compound II-1C3″ to obtain compound II-1C;

wherein, A, R¹⁻³ and R¹⁻⁴ are defined as above.

The conditions and steps of the reaction described in method A may beconventional conditions and steps in the art. The following reactionconditions are particularly preferred in the present disclosure:

Step I, the amino protecting group PG may be any suitable aminoprotecting group commonly used in the art, preferably Cbz, which isintended to protect compound II-1C1 from certain reactive groups (e.g.,amino groups) on it when it is involved in the reaction. The compoundII-1C1 is preferably a bromide or an iodide.

Step II, the Suzuki reaction conditions are any suitable reactionconditions commonly used in the art. The Suzuki reaction conditions arepreferably Pd(Ph₃P)₄ or Pd(dppf)Cl₂, potassium carbonate,1,2-dimethoxyethane or dioxane.

Step III, the ketal removal conditions are any suitable reactionconditions commonly used in the art, the removal is preferably carriedout using hydrochloric acid, and the reaction temperature is preferably50° C.-100° C.

Step IV, the reductive amination reaction conditions are any suitablereaction conditions commonly used in the art, and the reducing agent ispreferably sodium triacetoxyborohydride.

Step V, the conditions for removing the amino protection group PG withthe reducing agent and simultaneously reducing the double bond can bethe conventional conditions of the method in the art. The aminoprotecting group PG, such as benzyl or Cbz, preferably Cbz. The reducingagent is preferably palladium carbon/hydrogen.

The conditions and steps of the reaction described in method B may beconventional conditions and steps in the art. The following reactionconditions are particularly preferred in the present disclosure:

Step I, the Suzuki reaction conditions are any suitable reactionconditions commonly used in the art. The Suzuki reaction conditions arepreferably Pd(Ph₃P)₄ or Pd(dppf)Cl₂, potassium carbonate,1,2-dimethoxyethane or dioxane.

Step II, the reduction reaction conditions are any suitable reactionconditions commonly used in the art to reduce both nitro and doublebonds, such as palladium carbon/hydrogen, palladium carbon/ammoniumformate, palladium carbon/hydrazine hydrate.

The conditions and steps of the reaction described in method C may beconventional conditions and steps in the art. The following reactionconditions are particularly preferred in the present disclosure:

Step I, the reductive amination reaction conditions are any suitablereaction conditions commonly used in the art, and the reducing agent ispreferably sodium triacetoxyborohydride.

Step II, the Buchwald reaction conditions are any suitable reactionconditions commonly used in the art. The Buchwald reaction conditionsare preferably Pd₂(dba)₃/sodium tert-butoxide/Binap.

Step III, the reaction conditions for removing diphenyl are any suitablereaction conditions commonly used in the art, and the reactionconditions are preferably sodium acetate/hydroxylamine hydrochloride.

The present disclosure also provides a preparation method of thecompound I, which is any of the following methods:

method 1, comprising the following steps: step I, oxidizing compound 1Awith an oxidant in an organic solvent to obtain compound 1B; step II,reacting compound 1B with compound 1C in an organic solvent and underalkaline conditions to obtain compound I;

method 2, comprising the following steps: step I, hydrolyzing compound2A (R¹ is —(C═O)—O—C₂H₅) to obtain compound 2B (R¹ is —(C═O)—OH); stepII, an condensation reaction is carried out between compound 2B and anamino compound in an organic solvent to obtain compound I (R¹ is—(C═O)—NR¹⁻⁵⁻¹R¹⁻⁵⁻²);

The conditions and steps of the reaction described in method 1 may beconventional conditions and steps in the art. The following reactionconditions are particularly preferred in the present disclosure:

Step 1, the organic solvent is preferably one or more of methanol,dichloromethane, acetonitrile, toluene and DMF, more preferablydichloromethane or toluene; the oxidant may be an oxidant commonly usedin the art to oxidize thioether to sulfoxide, preferablym-chloroperoxybenzoic acid (m-CPBA); the molar ratio of compound 1A tom-CPBA is preferably 1: (1-1.2), the reaction time is preferably 1-12hours, and the reaction temperature is preferably 0° C.-35° C.

Step 2, the organic solvent is preferably dichloromethane or toluene;the alkaline condition is preferably an organic base such asN,N-diisopropylethylamine (DIPEA) or triethylamine, more preferablyN,N-diisopropylethylamine (DIPEA); the molar ratio of compound 1B,compound 1C and DIPEA is preferably 1:1:2, the reaction time ispreferably 0-12 hours, and the reaction temperature is preferably 0°C.-35° C.

The conditions and steps of the reaction described in method 2 may beconventional conditions and steps in the art. The following reactionconditions are particularly preferred in the present disclosure:

Step 1, the hydrolysis reaction conditions are any suitable reactionconditions commonly used in the art, such as alkaline hydrolysis or acidhydrolysis, and alkaline hydrolysis is for example sodium hydroxidehydrolysis or lithium hydroxide hydrolysis.

Step 2, the amino compound may be a primary or secondary amine; theorganic solvent is preferably dichloromethane or DMF; the condensationreaction is carried out under any suitable reaction conditions commonlyused in the art, such as EDCI/HOBT/DIPEA or HATU/DIPEA.

The present disclosure also provides a compound represented by formula1C:

wherein, A is C₃-C₂₀ cycloalkyl substituted by one R¹, R¹ is —NR¹⁻³R¹⁻⁴or —C(═O)R¹⁻⁵, and the R¹⁻³, R¹⁻⁴ and R¹⁻⁵ are defined as above.

In a certain scheme, the compound represented by formula 1C may be anyof the following compounds:

In a certain scheme, the compound represented by formula 1C may be anyof the following compounds:

its ¹H NMR (400 MHz, CDCl₃) is δ 7.08-6.96 (m, 2H), 6.70-6.60 (m, 2H),3.57 (s, 2H), 3.22 (t, J=7.0 Hz, 4H), 2.38 (tt, J=12.1, 3.2 Hz, 1H),2.15-1.95 (m, 5H), 1.95-1.81 (m, 4H), 1.51-1.30 (m, 2H), 1.21-1.04 (m,2H);

or,

its ¹H NMR (400 MHz, MeOD) is δ 7.10-6.97 (m, 2H), 6.74-6.63 (m, 2H),4.22-4.08 (t, J=8.0 Hz, 4H), 3.47-3.38 (m, 1H), 2.61-2.52 (m, 1H),2.52-2.28 (m, 2H), 1.92-1.62 (m, 8H).

The present disclosure also provides a preparation method of thecompound represented by formula 1C, which is any of the followingmethods:

method A: step I, protecting amino N of compound 1C1 in an organicsolvent under alkaline condition to obtain compound 1C2; step II, aSuzuki reaction is carried out between compound 1C2 and compound 1C3 toobtain compound 1C4; step III, removing the ketal of compound 1C4 toobtain compound 1C5; step IV. a reductive amination reaction is carriedout with compound 1C5 to obtain compound 1C6; step V, removing the aminoprotecting group PG of the compound 1C6 with a reducing agent andreducting the double bond simultaneously to obtain compound 1C;

wherein, PG is an amino protecting group, R is —NR¹⁻³R¹⁻⁴, and R¹⁻³ andR¹⁻⁴ are defined as above;

method B, comprising the following steps: step I, a Suzuki reaction iscarried out between compound 1C′ and compound 1C2′ to obtain compound1C3′; step II, a reduction reaction is carried out with compound 1C3′ toobtain compound 1C;

wherein, R¹ is —C(═O)R¹⁻⁵, R¹⁻⁵ is defined as above;

method C, comprising the following steps: step I, a reductive aminationreaction is carried out with compound 1C1″ (ring A is oxo-C₄-C₆cycloalkyl) to obtain compound 1C2″ (R¹ is —NR¹⁻³R¹⁻⁴); step II, aBuchwald reaction is carried out between compound 1C2′ and benzophenoneimine to obtain compound 1C3′ (R¹ is —NR¹⁻³R¹⁻⁴); step III, removing thediphenyl of compound 1C3″ to obtain compound 1C;

wherein, A, R¹⁻³ and R¹⁻⁴ are defined as above.

The conditions and steps of the reaction described in method A may beconventional conditions and steps in the art. The following reactionconditions are particularly preferred in the present disclosure:

Step I, the amino protecting group PG may be any suitable aminoprotecting group commonly used in the art, preferably Cbz, which isintended to protect compound 1C1 from certain reactive groups (e.g.,amino groups) on it when it is involved in the reaction. The compound1C1 is preferably a bromide or an iodide.

Step II, the Suzuki reaction conditions are any suitable reactionconditions commonly used in the art. The Suzuki reaction conditions arepreferably Pd(Ph₃P)₄ or Pd(dppf)Cl₂, potassium carbonate,1,2-dimethoxyethane or dioxane.

Step III, the ketal removal conditions are any suitable reactionconditions commonly used in the art, the removal is preferably carriedout using hydrochloric acid, and the reaction temperature is preferably50° C.-100° C.

Step IV, the reductive amination reaction conditions are any suitablereaction conditions commonly used in the art, and the reducing agent ispreferably sodium triacetoxyborohydride.

Step V, the conditions for removing the amino protection group PG withthe reducing agent and simultaneously reducing the double bond can bethe conventional conditions of the method in the art. The aminoprotecting group PG, such as benzyl or Cbz, preferably Cbz. The reducingagent is preferably palladium carbon/hydrogen.

The conditions and steps of the reaction described in method B may beconventional conditions and steps in the art. The following reactionconditions are particularly preferred in the present disclosure:

Step I, the Suzuki reaction conditions are any suitable reactionconditions commonly used in the art. The Suzuki reaction conditions arepreferably Pd(Ph₃P)₄ or Pd(dppf)Cl₂, potassium carbonate,1,2-dimethoxyethane or dioxane.

Step II, the reduction reaction conditions are any suitable reactionconditions commonly used in the art to reduce both nitro and doublebonds, such as palladium carbon/hydrogen, palladium carbon/ammoniumformate, palladium carbon/hydrazine hydrate.

The conditions and steps of the reaction described in method C may beconventional conditions and steps in the art. The following reactionconditions are particularly preferred in the present disclosure:

Step I, the reductive amination reaction conditions are any suitablereaction conditions commonly used in the art, and the reducing agent ispreferably sodium triacetoxyborohydride.

Step II, the Buchwald reaction conditions are any suitable reactionconditions commonly used in the art. The Buchwald reaction conditionsare preferably Pd₂(dba)₃/sodium tert-butoxide/Binap.

Step III. the reaction conditions for removing diphenyl are any suitablereaction conditions commonly used in the art, and the reactionconditions are preferably sodium acetate/hydroxylamine hydrochloride.

The present disclosure also provides an application of a substance X inthe preparation of kinase inhibitors (such as WEE1 kinase);

the substance X is the pyrazolone-fused pyrimidine compound representedby formula II, the pharmaceutically acceptable salt thereof, the solvatethereof, the solvate of the pharmaceutically acceptable salt thereof,the metabolite thereof or the prodrug thereof.

The present disclosure also provides an application of the substance Xin the manufacture of a medicament;

the substance X is the pyrazolone-fused pyrimidine compound representedby formula II, the pharmaceutically acceptable salt thereof, the solvatethereof, the solvate of the pharmaceutically acceptable salt thereof,the metabolite thereof or the prodrug thereof.

The present disclosure also provides an application of the substance Xin the manufacture of a medicament; the medicament is used for treatingand/or preventing diseases related to WEE1 kinase;

the substance X is the pyrazolone-fused pyrimidine compound representedby formula II, the pharmaceutically acceptable salt thereof, the solvatethereof, the solvate of the pharmaceutically acceptable salt thereof,the metabolite thereof or the prodrug thereof.

The diseases related to WEE1 kinase such as cancer. The cancers are forexample brain cancer, head and neck cancer, esophageal cancer, thyroidcancer, small cell cancer, non-small cell cancer, breast cancer, lungcancer, stomach cancer, gallbladder-cholangiocarcinoma, liver cancer,pancreatic cancer, colon cancer, rectal cancer, ovarian cancer,choriocarcinoma, endometrial carcinoma, cervical cancer, renalpelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer,testicular cancer, embryonal carcinoma, nephroblastoma, skin cancer,malignant melanoma, neuroblastoma, osteosarcoma, ewing tumor, softtissue tumor, acute leukemia, chronic lymphatic leukemia, chronicmyeloid leukemia or Hodgkin's lymphoma, for example, breast cancer, lungcancer, pancreatic cancer, colon cancer, ovarian cancer, acute leukemia,chronic lymphatic leukemia, chronic myeloid leukemia, Hodgkin'slymphoma, for example, colon or ovarian cancer.

The present disclosure also provides an application of the substance Xin the manufacture of a medicament; the medicament is used for treatingand/or preventing cancer;

the substance X is the pyrazolone-fused pyrimidine compound representedby formula II, the pharmaceutically acceptable salt thereof, the solvatethereof, the solvate of the pharmaceutically acceptable salt thereof,the metabolite thereof or the prodrug thereof.

The cancers are for example brain cancer, head and neck cancer,esophageal cancer, thyroid cancer, small cell cancer, non-small cellcancer, breast cancer, lung cancer, stomach cancer,gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, coloncancer, rectal cancer, ovarian cancer, choriocarcinoma, endometrialcarcinoma, cervical cancer, renal pelvis-ureteral cancer, bladdercancer, prostate cancer, penile cancer, testicular cancer, embryonalcarcinoma, nephroblastoma, skin cancer, malignant melanoma,neuroblastoma, osteosarcoma, ewing tumor, soft tissue tumor, acuteleukemia, chronic lymphatic leukemia, chronic myeloid leukemia orHodgkin's lymphoma, for example, breast cancer, lung cancer, pancreaticcancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphaticleukemia, chronic myeloid leukemia, Hodgkin's lymphoma, for example,colon or ovarian cancer.

The present disclosure also provides a method for treating and/orpreventing diseases related to WEE1 kinase comprising administering atherapeutically effective amount of the substance X to a patient;

the substance X is the pyrazolone-fused pyrimidine compound representedby formula II, the pharmaceutically acceptable salt thereof, the solvatethereof, the solvate of the pharmaceutically acceptable salt thereof,the metabolite thereof or the prodrug thereof.

The diseases related to WEE1 kinase such as cancer. The cancers are forexample brain cancer, head and neck cancer, esophageal cancer, thyroidcancer, small cell cancer, non-small cell cancer, breast cancer, lungcancer, stomach cancer, gallbladder-cholangiocarcinoma, liver cancer,pancreatic cancer, colon cancer, rectal cancer, ovarian cancer,choriocarcinoma, endometrial carcinoma, cervical cancer, renalpelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer,testicular cancer, embryonal carcinoma, nephroblastoma, skin cancer,malignant melanoma, neuroblastoma, osteosarcoma, ewing tumor, softtissue tumor, acute leukemia, chronic lymphatic leukemia, chronicmyeloid leukemia or Hodgkin's lymphoma, for example, breast cancer, lungcancer, pancreatic cancer, colon cancer, ovarian cancer, acute leukemia,chronic lymphatic leukemia, chronic myeloid leukemia, Hodgkin'slymphoma, for example, colon or ovarian cancer.

The present disclosure also provides a method for treating and/orpreventing cancer comprising administering a therapeutically effectiveamount of the substance X to a patient;

the substance X is the pyrazolone-fused pyrimidine compound representedby formula II, the pharmaceutically acceptable salt thereof, the solvatethereof, the solvate of the pharmaceutically acceptable salt thereof,the metabolite thereof or the prodrug thereof.

The cancers are for example brain cancer, head and neck cancer,esophageal cancer, thyroid cancer, small cell cancer, non-small cellcancer, breast cancer, lung cancer, stomach cancer,gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, coloncancer, rectal cancer, ovarian cancer, choriocarcinoma, endometrialcarcinoma, cervical cancer, renal pelvis-ureteral cancer, bladdercancer, prostate cancer, penile cancer, testicular cancer, embryonalcarcinoma, nephroblastoma, skin cancer, malignant melanoma,neuroblastoma, osteosarcoma, ewing tumor, soft tissue tumor, acuteleukemia, chronic lymphatic leukemia, chronic myeloid leukemia orHodgkin's lymphoma, for example, breast cancer, lung cancer, pancreaticcancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphaticleukemia, chronic myeloid leukemia, Hodgkin's lymphoma, for example,colon or ovarian cancer.

The present disclosure also provides a pharmaceutical compositioncomprising the substance X and (one or more) pharmaceutical excipients;

the substance X is the pyrazolone-fused pyrimidine compound representedby formula II, the pharmaceutically acceptable salt thereof, the solvatethereof, the solvate of the pharmaceutically acceptable salt thereof,the metabolite thereof or the prodrug thereof.

The present disclosure also provides a combination comprising thesubstance X and an anticancer drug, the substance X is thepyrazolone-fused pyrimidine compound represented by formula II, thepharmaceutically acceptable salt thereof, the solvate thereof, thesolvate of the pharmaceutically acceptable salt thereof, the metabolitethereof or the prodrug thereof.

The anticancer drugs may be a conventional anticancer drug in the art(but not substance X as described above), such as one or more ofanticancer alkylating agents, anticancer metabolic antagonists,anticancer antibiotics, anticancer drugs derived from plant, anticancerplatinum ligand compounds, anticancer camptothecin derivatives,anticancer tyrosine kinase inhibitors, monoclonal antibodies,interferons, biological response modifiers, mitoxantrone,L-asparaginase, procarbazine, dacarbazine, hydroxyurea, pentostatin,retinoic acid, alefacept, darbepoetin alfa, anastrozole, exemestane,bicalutamide, leuprolide, flutamide, fulvestrant, pegaptanib sodium,denileukin diftitox 2, aldesleukin, thyrotropina, arsenic trioxide,bortezomib, capecitabine and goserelin, for example, anticancermetabolic antagonists.

The anticancer alkylating agent may be a conventional anticanceralkylating agent in the art, such as one or more of mechlorethanmineN-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan,dibromomannitol, carboquone, thiotepa, ranimustine, nimustine,temozolomide and carmustine.

The anticancer metabolic antagonist may be a conventional anticancermetabolic antagonist in the art, such as one or more of methotrexate,6-mercaptopurine nucleoside, mercaptopurine, 5-fluorouracil, tegafur,doxifluridine, carmofur, cytarabine, cytarabine octadecyl sodiumphosphate, enocitabine, S-1, gemcitabine, fludarabine and pemetrexeddisodium, such as 5-fluorouracil.

The anticancer antibiotic may be a conventional anticancer antibiotic inthe art, such as one or more of actinomycin D, doxorubicin,daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C,aclarubicin, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin,sirolimus, and valrubicin.

The anticancer drug derived from plants may be a conventional anticancerdrug derived from plants in the art, such as one or more of vincristine,vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel andvinorelbine.

The anticancer platinum coordination compound may be a conventionalanticancer platinum coordination compound in the art, such as one ormore of cisplatin, carboplatin, nedaplatin and oxaliplatin.

The anticancer camptothecin derivative may be a conventional anticancercamptothecin derivative in the art, such as one or more of irinotecan,topotecan and camptothecin.

The anticancer tyrosine kinase inhibitor may be a conventionalanticancer tyrosine kinase inhibitor in the art, such as one or more ofgefitinib, imatinib and erlotinib.

The monoclonal antibody may be a conventional monoclonal antibody in theart, such as one or more of cetuximab, bevacizumab, rituximab,alemtuzumab and trastuzumab.

The interferon may be a conventional interferon in the art, such as oneor more of interferon α, interferon α-2a, interferon α-2b, interferon β,interferon γ-1a and interferon γ-n1.

The biological response regulator may be a conventional biologicalresponse regulator in the art, such as one or more of coriolusversicolor polysaccharide, lentinan, sizofiran, sapylin and ubenimex.

The components in the combination can be used simultaneously orseparately (for example, sequentially); when the components in thecombination are used simultaneously, the components in the combinationcan be uniformly mixed (e.g., the mixture of the components).

The components of the combination may be prepared as a singlepharmaceutical composition for simultaneous use, or the components maybe individually prepared as a single independent pharmaceuticalcomposition (e.g., in kit form), which may be used simultaneously orseparately (e.g., sequentially).

The present disclosure also provides an application of the abovecombination in the preparation of a medicament for preventing and/ortreating cancer.

The cancers are for example brain cancer, head and neck cancer,esophageal cancer, thyroid cancer, small cell cancer, non-small cellcancer, breast cancer, lung cancer, stomach cancer,gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, coloncancer, rectal cancer, ovarian cancer, choriocarcinoma, endometrialcarcinoma, cervical cancer, renal pelvis-ureteral cancer, bladdercancer, prostate cancer, penile cancer, testicular cancer, embryonalcarcinoma, nephroblastoma, skin cancer, malignant melanoma,neuroblastoma, osteosarcoma, ewing tumor, soft tissue tumor, acuteleukemia, chronic lymphatic leukemia, chronic myeloid leukemia orHodgkin's lymphoma, for example, breast cancer, lung cancer, pancreaticcancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphaticleukemia, chronic myeloid leukemia, Hodgkin's lymphoma, for example,colon or ovarian cancer.

In the application of the present disclosure, the above substance X andthe above anticancer drugs can be administered simultaneously orseparately (for example, sequentially).

The present disclosure also provides a method for treating and/orpreventing cancer comprising administering a therapeutically effectiveamount of the above combination to a patient.

The anticancer drug can be as described above.

The cancers are for example brain cancer, head and neck cancer,esophageal cancer, thyroid cancer, small cell cancer, non-small cellcancer, breast cancer, lung cancer, stomach cancer,gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, coloncancer, rectal cancer, ovarian cancer, choriocarcinoma, endometrialcarcinoma, cervical cancer, renal pelvis-ureteral cancer, bladdercancer, prostate cancer, penile cancer, testicular cancer, embryonalcarcinoma, nephroblastoma, skin cancer, malignant melanoma,neuroblastoma, osteosarcoma, ewing tumor, soft tissue tumor, acuteleukemia, chronic lymphatic leukemia, chronic myeloid leukemia orHodgkin's lymphoma, for example, breast cancer, lung cancer, pancreaticcancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphaticleukemia, chronic myeloid leukemia, Hodgkin's lymphoma, for example,colon or ovarian cancer.

The present disclosure also provides an application of the abovesubstance X in the preparation of a medicament, the medicament incombination with an anticancer drug used for preventing and/or treatingcancer.

The anticancer drug can be as described above.

The cancers are for example brain cancer, head and neck cancer,esophageal cancer, thyroid cancer, small cell cancer, non-small cellcancer, breast cancer, lung cancer, stomach cancer,gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, coloncancer, rectal cancer, ovarian cancer, choriocarcinoma, endometrialcarcinoma, cervical cancer, renal pelvis-ureteral cancer, bladdercancer, prostate cancer, penile cancer, testicular cancer, embryonalcarcinoma, nephroblastoma, skin cancer, malignant melanoma,neuroblastoma, osteosarcoma, ewing tumor, soft tissue tumor, acuteleukemia, chronic lymphatic leukemia, chronic myeloid leukemia orHodgkin's lymphoma, for example, breast cancer, lung cancer, pancreaticcancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphaticleukemia, chronic myeloid leukemia, Hodgkin's lymphoma, for example,colon or ovarian cancer.

In the application of the present disclosure, the above substance X andthe above anticancer drugs can be administered simultaneously orseparately (for example, sequentially).

The present disclosure also provides an anticancer drug in thepreparation of a medicament, the medicament in combination with thesubstance X used for preventing and/or treating cancer.

The anticancer drug can be as described above.

The cancers are for example brain cancer, head and neck cancer,esophageal cancer, thyroid cancer, small cell cancer, non-small cellcancer, breast cancer, lung cancer, stomach cancer,gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, coloncancer, rectal cancer, ovarian cancer, choriocarcinoma, endometrialcarcinoma, cervical cancer, renal pelvis-ureteral cancer, bladdercancer, prostate cancer, penile cancer, testicular cancer, embryonalcarcinoma, nephroblastoma, skin cancer, malignant melanoma,neuroblastoma, osteosarcoma, ewing tumor, soft tissue tumor, acuteleukemia, chronic lymphatic leukemia, chronic myeloid leukemia orHodgkin's lymphoma, for example, breast cancer, lung cancer, pancreaticcancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphaticleukemia, chronic myeloid leukemia, Hodgkin's lymphoma, for example,colon or ovarian cancer.

In the application of the present disclosure, the above substance X andthe above anticancer drugs can be administered simultaneously orseparately (for example, sequentially).

The present disclosure also provides a pharmaceutical compositioncomprising the above combination and (one or more) pharmaceuticalexcipients.

The pharmaceutical composition can be composed of the combination andthe pharmaceutical excipients.

The present disclosure also provides a combination drug kit comprising apharmaceutical composition A and a pharmaceutical composition B;

the pharmaceutical composition A comprises the above substance X, and(one or more) pharmaceutical excipients;

the pharmaceutical composition B comprises the anticancer drugs and oneor more pharmaceutical excipients.

The anticancer drug can be as described above.

The combination drug kit can be composed of the pharmaceuticalcomposition A and the pharmaceutical composition B.

The pharmaceutical composition A can be composed of the substance X, and(one or more) pharmaceutical excipients;

the pharmaceutical composition B can be composed of the anticancer drugsand one or more pharmaceutical excipients.

Each pharmaceutical composition in the combination drug kit can be usedsimultaneously or separately (for example, sequentially).

Unless otherwise specified, the following terms appearing in the presentspecification and claims have the following meanings:

The term “pharmaceutically acceptable” means that salts, solvents,excipients, etc. are generally nontoxic, safe and suitable for patientuse. The “patient” is preferably a mammal, more preferably a human.

The term “pharmaceutically acceptable salt” refers to the salt preparedby the compound of the present disclosure and a relatively nontoxic andpharmaceutically acceptable acid or base. When the compound of thepresent disclosure contains a relatively acidic functional group, a baseaddition salt can be obtained by bringing the neutral form of thecompound into contact with a sufficient amount of a pharmaceuticallyacceptable base in a pure solution or a suitable inert solvent. Thepharmaceutically acceptable base addition salts include, but are notlimited to, lithium salts, sodium salts, potassium salts, calcium salts,aluminum salts, magnesium salts, zinc salts, bismuth salts, ammoniumsalts, and diethanolamine salts. When the compound of the presentdisclosure contains a relatively basic functional group, an acidaddition salt can be obtained by bringing the neutral form of thecompound into contact with a sufficient amount of a pharmaceuticallyacceptable acid in a pure solution or a suitable inert solvent. Thepharmaceutically acceptable acids include inorganic acids, the inorganicacids include but are not limited to hydrochloric acid, hydrobromicacid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid,phosphorous acid, sulfuric acid, etc. The pharmaceutically acceptableacids include organic acids, the organic acids including but not limitedto: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleicacid, malonic acid, benzoic acid, succinic acid, octanedioic acid,trans-butenedioic acid, lactic acid, mandelic acid, phthalic acid,benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylicacid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidcitric acid, oleic acid, tannic acid, pantothenic acid, hydrogentartrate, ascorbic acid, gentianic acid, fumaric acid, gluconic acid,saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e.,4,4′-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acid (e.g.,glutamic acid, arginine), etc. When the compounds of the presentdisclosure contain relatively acidic and basic functional groups, theycan be converted into base addition salts or acid addition salts. SeeBerge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science66: 1-19 (1977) or Handbook of Pharmaceutical Salts: Properties,Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed.,Wiley-VCH, 2002).

The term “solvate” refers to a substance formed by together a compoundof the present disclosure with a stoichiometric or non-stoichiometricsolvent. Solvent molecules in solvates can exist in the form of orderedor unordered arrangement. The solvents include but are not limited to:water, methanol, ethanol, etc.

The terms “pharmaceutically acceptable salts” and “solvates” in theterms “solvates of pharmaceutically acceptable salts”, as describedabove, refer to compound of the present disclosure, 1. prepared with arelatively nontoxic, pharmaceutically acceptable acid or base, and 2.formed in combination with a stoichiometric or non-stoichiometricsolvent. The “solvates of pharmaceutically acceptable salts” include butare not limited to hydrochloric acid monohydrate of the compound of thepresent disclosure.

The terms “compound”, “pharmaceutically acceptable salt”, “solvate” and“solvate of pharmaceutically acceptable salt” can exist in crystallineor amorphous form. The term “crystalline” means that the ions ormolecules in it are arranged in a defined way in a three-dimensionalspace in a strictly periodic manner, and have a regular pattern ofperiodic recurrence at a certain distance apart; because of the aboveperiodic arrangement, there can be a variety of crystalline forms, thatis, the phenomenon of polycrystalline forms. The term “amorphous” refersto the disordered distribution of ions or molecules, that is, there isno periodic arrangement between ions and molecules.

The terms “compound”, “pharmaceutically acceptable salt”, “solvate” and“solvate of pharmaceutically acceptable salt” may exist in the form of asingle stereoisomer or a mixture thereof (e.g. racemate), ifstereoisomers exist. The term “stereoisomer” refers to cis-trans isomeror optical isomer. These stereoisomers can be separated, purified andenriched by asymmetric synthesis or chiral separation methods (includingbut not limited to thin layer chromatography, rotary chromatography,column chromatography, gas chromatography, high pressure liquidchromatography, etc.), and can also be obtained by chiral resolution bybonding (chemical bonding, etc.) or salting (physical bonding, etc.)with other chiral compounds. The term “single stereoisomer” means thatone stereoisomer of a compound of the present disclosure is not lessthan 95% by mass relative to all stereoisomers of the compound.

The terms “compound”, “pharmaceutically acceptable salt”, “solvate” and“solvate of pharmaceutically acceptable salt” may exist in the form ofsingle tautomer or a mixture thereof, preferably in the form in whichthe more stable tautomer is predominant.

The terms “compound”, “pharmaceutically acceptable salt”, “solvate” and“solvate of pharmaceutically acceptable salt” can exist in their naturalabundance or unnatural abundance. Taking hydrogen atom as an example,its natural abundance form means that about 99.985% is protium and about0.015% is deuterium; in the form of unnatural abundance, for example,about 95% of which is deuterium. That is, one or more atoms in the terms“compound”, “pharmaceutically acceptable salt”, “solvate” and “solvateof pharmaceutically acceptable salt” may be atoms that exist inunnatural abundance.

When an arbitrary variable (e.g. R¹⁻¹⁻¹) occurs many times in thedefinition of a compound, the definition of each position of thevariable is independent of the definition of the rest, and theirmeanings are independent of each other and do not affect each other.Therefore, if a certain group is substituted by one, two or three R¹⁻¹⁻¹groups, that is to say, the group may be substituted by up to threeR¹⁻¹⁻¹ groups, the definition of R¹⁻¹⁻¹ at this position is independentfrom that of the R¹⁻¹⁻¹. In addition, the combination of substituentsand/or variables is allowed only when the combination produces a stablecompound.

The term “optionally substituted” means that it may or may not besubstituted.

The term “halogen” refers to fluorine, chlorine, bromine or iodine.

The term “alkyl” refers to a saturated linear or branched monovalenthydrocarbon group having one to twelve carbon atoms (e.g. C₁-C₆ alkyl,e.g. C₁-C₄ alkyl). Examples of alkyl include, but are not limited to,methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-butyl,2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl,3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl,3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl,3,3-dimethyl-2-butyl, 1-heptyl, and 1-octyl.

The term “alkenyl” refers to a linear or branched monovalent hydrocarbongroup having two to twelve carbon atoms with at least one unsaturatedposition, i.e., a carbon-carbon sp² double bond (e.g. C₂-C₆ alkenyl,e.g. C₂-C₄ alkenyl), and includes groups with “cis” and “trans”orientations or “E” and “Z” orientations. Examples include, but are notlimited to, vinyl, allyl.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbongroup having two to twelve carbon atoms with at least one unsaturatedposition, i.e., a carbon-carbon sp triple bond (e.g. C₂-C₆ alkynyl, e.g.C₂-C₄ alkynyl). Examples include, but are not limited to, ethynyl andpropynyl.

The term “cycloalkyl” refers to a saturated or partially unsaturated(containing one or two double bonds) non-aromatic cyclic hydrocarbongroup (e.g. C₃-C₆ cycloalkyl) with three to twenty carbon atoms,including monocyclic cycloalkyl and polycyclic cycloalkyl. Thecycloalkyl group contains 3 to 20 carbon atoms, preferably 3 to 12carbon atoms, more preferably 3 to 6 carbon atoms.

Examples of monocyclic cycloalkyl include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 5-hexenyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

Polycyclic cycloalkyl are polycyclic (e.g., bicyclic and tricyclic)cycloalkyl structures, including spiro cycloalkyl, fused cycloalkyl andbridged cycloalkyl. Wherein, “spiro cycloalkyl” refers to a polycyclicgroup sharing one carbon atom (called spiro atom) between the singlerings of 5 to 20 membered, which may contain one or more double bonds,but none of the rings has a fully conjugated 1 L electron system.Preferably 6 to 14 membered, more preferably 7 to 10 membered. Accordingto the number of spiro cycloalkyl shared between rings, the spirocycloalkyl is divided into monospiro cycloalkyl, bisspiro cycloalkyl orpolyspiro cycloalkyl, preferably monospiro cycloalkyl and bisspirocycloalkyl. More preferably 4 membered/4 membered, 4 membered/5membered, 4 membered/6 membered, 5 membered/5 membered or 5membered/6-membered monospiro cycloalkyl. Examples of spiro cycloalkylinclude, but are not limited to:

Wherein, “fused cycloalkyl” refers to all-carbon polycyclic groups of 5to 20 membered, each ring in the system sharing an adjacent pair ofcarbon atoms with other rings in the system, which may contain one ormore double bonds, but none of the rings has a fully conjugated7-electron system. Preferably 6 to 14 membered, more preferably 7 to 10membered. According to the number of constituent rings, it can bedivided into bicyclic, tricyclic, tetracyclic or polycyclic fusedcycloalkyl, preferably bicyclic or tricyclic, more preferably5-membered/5-membered or 5-membered/6-membered bicyclic cycloalkyl.Examples of fused cycloalkyl include, but are not limited to:

“Bridged cycloalkyl” refers to all-carbon polycyclic group of 5 to 20members, any two rings share two non-directly connected carbon atoms,which may contain one or more double bonds, but none of which has acompletely conjugated π-electron system. Preferably 6 to 14 membered,more preferably 7 to 10 membered. According to the number of constituentrings, it can be divided into bicyclic, tricyclic, tetracyclic orpolycyclic bridged cycloalkyl, preferably bicyclic, tricyclic ortetracyclic, more preferably bicyclic or tricyclic. Examples of bridgedcycloalkyl include, but are not limited to:

The term “heterocycloalkyl” refers to a saturated carbocyclic grouphaving 3 to 20 ring atoms, wherein at least one ring atom is aheteroatom independently selected from boron, silicon, oxygen, sulfur,selenium, nitrogen and phosphorus, and the remaining ring atoms are C.The group may be a carbon group or a heteroatom group (i.e. it may beC-linked or N-linked, as long as it is possible). Examples ofheterocyclic groups include, but are not limited to, pyrrolidinyl,tetrahydrofuran, tetrahydrothiophene, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, 4-thiomorpholinyl,thioalkyl and piperazinyl. Fused ring portion, spiro ring portion andbridge ring portion are also included in the scope of this definition.For example, the group derived from tetrahydropyrrole can betetrahydropyrrol-1-yl (N-linked) or tetrahydropyrrol-3-yl (C-linked).For example a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3heteroatoms selected from N, O, P, B, Si, S and Se, where N, B, P or Seis optionally substituted by one or more oxygen atoms to obtain groupslike NO, BOH, PO, PO₂, SeO; N can be optionally quaternized; S atoms canbe optionally substituted by one or more oxygen or nitrogen atoms toobtain a group like SO, SO₂, S(═O)(═NR^(a)), S(═NR^(b)) or S(═NR^(c))₂,while R^(a), R^(b) and R^(c) are independently cyano, C₁-C₇ alkyl,C₃-C₁₄ cycloalkyl, “C₃-C₁₄ heterocycloalkyl having 1-4 heteroatoms andone or more heteroatoms of boron, silicon, oxygen, sulfur, selenium,nitrogen and phosphorus”, “C₁-C₇ heteroaryl having 1-4 heteroatoms andone or more heteroatoms of boron, silicon, oxygen, sulfur, selenium,nitrogen and phosphorus”, C₆-C₁₀ aryl or C₁-C₇ alkoxy; meanwhile, the—CH₂— group may be optionally substituted by —C(═O)—, —C(═S)— or—C(═NR^(d))—, R^(d) is independently cyano, C₁-C₇ alkyl, C₃-C₁₄cycloalkyl, “C₃-C₁₄ heterocycloalkyl having 1-4 heteroatoms and one ormore heteroatoms of boron, silicon, oxygen, sulfur, selenium, nitrogenand phosphorus”, “C₁-C₇ heteroaryl having 1-4 heteroatoms and one ormore heteroatoms of boron, silicon, oxygen, sulfur, selenium, nitrogenand phosphorus”, C₆-C₁₀ aryl or C₁-C₇ alkoxy; when the ring is a3-membered ring, only one heteroatom is present in the ring), or, abicyclic ring consisting of 7 to 10 atoms (4 to 9 carbon atoms and 1-3heteroatoms selected from N, O, P, B, Si, S, wherein N, S, B or P isoptionally substituted by one or more oxygen atoms to obtain groups likeNO, BOH, SO, SO₂, PO, PO₂, SeO, while —CH₂— group may be optionallysubstituted by —C(═O)—). Depending on the structure, the heterocyclylcan be a monovalent group or a divalent group, i.e., a subheterocyclyl.

The term “aryl” refers to any stable monocyclic or bicyclic carbon ringwith up to 10 atoms in each ring, wherein at least one of which is anaromatic ring. Examples of the above aryl units include phenyl,naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl,phenanthrenyl, anthryl or acenaphthyl. It will be understood that in thecase where the aryl substituent is a bicyclic substituent and one of therings is a non-aromatic ring the connection is made through the aromaticring.

The term “heteroaryl” refers to a stable monocyclic or bicyclic ringwith up to 7 atoms in each ring, wherein at least one ring is anaromatic ring and contains 1-4 heteroatoms selected from boron, silicon,oxygen, sulfur, selenium, nitrogen and phosphorus. Heteroaryl withinthis definition include, but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl,thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl,isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl,pyrimidinyl, pyrrolyl, tetrahydroquinolyl. “Heteroaryl” should also beunderstood to include any N-oxide derivative of a nitrogen-containingheteroaryl. In the case wherein the heteroaryl substituent is a bicyclicsubstituent and one ring is a non-aromatic ring or does not containheteroatoms, it can be understood that the connections are made througharomatic rings respectively. Heteroaromatic ring-fused aromatic ring andbicyclic heteroaromatic ring systems can be fused to form rings.Wherein, N, S, B, P or Se is optionally substituted by one or moreoxygen atoms to obtain groups like NO, SO, SO₂, BOH, PO, PO₂, SeO, andthe N atom can be quaternized. Heteroaryl can be attached to the mainstructure at any heteroatom or carbon atom to form stable compounds.Depending on the structure, heteroaryl can be monovalent groups ordivalent groups, i.e., heteroarylene.

The term “alkoxy” refers to an alkyl linked by an oxygen bridge; thealkyl is defined as above.

The term “alkylthiol” refers to an alkyl linked by a sulfur bridge; thealkyl is defined as above.

The term “indeterminate of cis-trans conformation” refers to cis ortrans.

The term “component” refers to each component of the combination of thepresent disclosure, i.e., the compound represented by formula I (or thecompound represented by formula II), the pharmaceutically acceptablesalt thereof, the solvate thereof, the solvate of the pharmaceuticallyacceptable salt thereof, the metabolite thereof or the prodrug thereof,or the anticancer drug.

The term “pharmaceutical excipients” refers to excipients and additivesused in drug production and prescription formulation, and refers to allsubstances contained in pharmaceutical preparations except activeingredients. See the Pharmacopoeia of the People's Republic of China(2015 Edition) Part IV or Handbook of Pharmaceutical Excipients (RaymondC Rowe, 2009 Sixth Edition).

The term “treatment” refers to therapeutic therapy. When referring to aspecific condition, treatment means (1) alleviating one or morebiological manifestations of the disease or condition, (2) interferingwith (a) one or more points in the biological cascade causing orcontributing to the condition or (b) one or more biologicalmanifestations of the condition, (3) ameliorating one or more symptoms,effects, or side effects associated with the condition or its treatment,or one or more symptoms, effects, or side effects, or (4) slowing thedevelopment of the condition or one or more biological manifestations ofthe condition.

The term “prevention” refers to a reduction in the risk of acquiring ordeveloping diseases or disorders.

The term “therapeutically effective amount” refers to the amount of acompound that is sufficient to effectively treat the diseases ordisorders described herein when administered to a patient. The“therapeutically effective amount” will vary according to the compound,the condition and its severity, and the age of the patient to betreated, but it can be adjusted by those skilled in the art as needed.

The term “patient” refers to any animal, preferably a mammal, preferablya human, to which the compound or composition is to be administered orhas been administered according to an embodiment of the presentdisclosure. The term “mammal” includes any mammal. Examples of mammalsinclude, but are not limited to, cattle, horses, sheep, pigs, cats,dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., withhumans being the most preferred.

The term “active ingredient” refers to the active ingredient in thepharmaceutical composition or combination kit of the present disclosure,i.e., the compound represented by formula I (or the compound representedby formula II), the pharmaceutically acceptable salt thereof, thesolvate thereof, the solvate of the pharmaceutically acceptable saltthereof, the metabolite thereof or the prodrug thereof, the anticancerdrug, or a combination thereof.

On the basis of not violating the common sense in the field, the abovepreferred conditions can be arbitrarily combined to obtain the preferredembodiments of the present disclosure.

The reagents and raw materials used in the present disclosure arecommercially available.

The positive progressive effect of the present disclosure is that: thecompounds of the present disclosure have better inhibitory activityagainst WEE1 kinase and have better bioavailability.

DETAILED DESCRIPTION OF THE EMBODIMENT

The present disclosure will be further illustrated by way of embodimentsbelow, but it is not limited to the scope of the embodiments. Theexperimental methods not specified in the specific conditions in thefollowing embodiments are selected according to the conventional methodsand conditions, or according to the commodity specifications.

The structures of all compounds of the present disclosure can beidentified by nuclear magnetic resonance (¹HNMR) and/or massspectrometry (MS).

¹H NMR chemical shift (6) was recorded in PPM (10⁻⁶). NMR was performedby Bruker AVANCE-400 spectrometer.

LC-MS was determined by Agilent 1200HPLC/6120 mass spectrometer.

HPLC was determined by Agilent 1260 high performance liquidchromatograph. Specific conditions of HPLC: mobile phase A: water (0.1%formic acid), mobile phase B: acetonitrile; column time: 15 min; columntype: Waters' Xselect, 5 μm, 4.6×250 mm.

The thin layer silica gel plate was Liangchen silicon source HSGF254 orQingdao GF254 silica gel plate. Column chromatography generally usesYantai Huanghai 200-300 mesh silica gel as carrier.

Embodiment 1

Step 1:

4-Bromoaniline (I-1-a) (58.1 mmol) was dissolved in toluene (250 mL);potassium carbonate (87.2 mmol) and benzyl chloroformate (87.2 mmol)were added to the reaction mixture, and the reaction mixture was stirredat room temperature for 16 hours. The reaction mixture was filtered, thefiltrate was evaporated to dryness to obtain a crude product, and thecrude product was washed with ethyl acetate to obtain the targetcompound benzyl (4-bromophenyl)carbamate (I-1-b)(15.2 g, 85.4%) as agray solid. LC-MS: m/z: (M+H)⁺=307.0.

Step 2:

Benzyl (4-bromophenyl)carbamate (16.0 mmol) (I-1-b) was dissolved in1,2-dimethoxyethane (50 mL); and4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane(represented by formula I-1-c) (16.0 mmol), sodium carbonate (42.0 mmol)and tetrakis(triphenylphosphine)palladium (1.6 mmol) were added to thereaction mixture, the reaction mixture was heated to 80° C. and stirredfor 16 hours. The reaction mixture was filtered, the filtrate wasevaporated to dryness to obtain a crude product, and the crude productwas purified by column chromatography(dichloromethane/methanol=100/0-95/5) to obtain the target compoundbenzyl (4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl)carbamate (I-1-d)(5.6 g, 94%) as a white solid. LC-MS: m/z: (M+H)⁺=366.2.

Step 3:

Benzyl (4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl)carbamate (I-1-d) (15mmol) was dissolved in tetrahydrofuran (15 mL). Hydrochloric acid (30.0mL, 4N) was added to the reaction mixture, and the reaction mixture wasstirred at 50° C. for 16 hours. The pH value of the reaction mixture wasadjusted to 9 with potassium carbonate, then the mixture was extractedwith dichloromethane, the organic phase was washed with saturatedsaline, dried over anhydrous sodium sulfate, filtered and evaporated todryness to obtain the crude target compound benzyl(4′-oxo-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)carbamate (I-1-e)(4.0 g, 81%) as a yellow solid. LC-MS: m/z: (M+H)⁺=322.1.

Step 4:

Benzyl (4′-oxo-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)carbamate(I-1-e) (12.0 mmol) was dissolved in dichloromethane (25 mL),dimethylamine hydrochloride (25.0 mmol) and diisopropylethylamine (25.0mmol) were added to the reaction mixture, and the reaction mixture wasstirred at room temperature for 2 hours, and sodiumtriacetoxyborohydride (37.0 mmol) was added to the reaction mixture,then the reaction mixture was stirred at room temperature for 16 hours.The pH value of the mixture was adjusted to 9 by adding saturatedpotassium carbonate aqueous solution, and the mixture was extracted withdichloromethane; then the organic phase was washed with saturatedsaline, dried over anhydrous sodium sulfate, filtered and evaporated todryness to obtain a crude product, and the crude product was purified bycolumn chromatography (dichloromethane/methanol=100/0-95/5) to obtainthe target compound benzyl(4′-(dimethylamino)-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)carbamate(I-1-f) (3.5 g, 80%) as a yellow solid. LC-MS: m/z: (M+H)⁺=351.2.

Step 5:

Benzyl(4′-(dimethylamino)-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)carbamate(I-1-f) (10.0 mmol) was dissolved in methanol (20 mL), palladium carbon(0.35 g) was added thereto, and the reaction mixture was stirred underhydrogen at room temperature for 16 hours. The reaction mixture wasfiltered, and the filtrate was evaporated to dryness to obtain a crudeproduct, the crude product was washed with ethyl acetate and filtered,and the filter cake was the target compound4-(4-(dimethylamino)cyclohexyl)aniline (I-1-g)(1.20 g, 55%) as a whitesolid. LC-MS: m/z: (M+H)⁺=219.2.

Step 6:

2-(1,1-Difluoroallyl)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(represented by formula I-1-h) (150 mg, 0.42 mmol) was dissolved intoluene (20 mL), 3-chlorophenoxyformic acid (105 mg, 0.47 mmol) wasadded thereto, and the reaction mixture was stirred at room temperaturefor 0.5 hours, then the reaction mixture was evaporated to dryness, theobtained sulfoxide intermediate was dissolved in dimethyl sulfoxide (10mL); 4-(4-methylpiperazin-1-yl)aniline (120 mg, 0.55 mmol) andtrifluoroacetic acid (0.2 mL) were added thereto, and the reactionmixture was heated to 60° C. and stirred for 24 hours. The pH value ofthe reaction mixture was adjusted to 9 with saturated sodium carbonatesolution, water (50 mL) and dichloromethane (50 mL) were added thereto,the phases were separated, and the organic phase was washed withsaturated saline, dried over anhydrous sodium sulfate, filtered,evaporated to dryness, prepared and purified in liquid phase to obtaincompound I-1-1 and compound I-1-2. Compound I-1-1: HPLC retention time(RT)=10.55 min (HPLC conditions: gradient elution, 5% mobile phase B→50%mobile phase B), the yield of the compound was 56% (110 mg) as a whitesolid: ¹H NMR (400 MHz, MeOD) δ 8.85 (s, 1H), 8.46 (s, 2H), 7.99 (t,J=7.9 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.65 (dd, J=16.6, 8.1 Hz, 3H),7.22 (d, J=8.6 Hz, 2H), 5.73 (ddt, J=16.3, 10.2, 6.1 Hz, 1H), 5.05 (dd,J=10.3, 1.1 Hz, 1H), 4.93 (dd, J=17.1, 1.3 Hz, 1H), 4.82 (d, J=6.1 Hz,2H), 2.90 (s, 6H), 2.60 (d, J=8.4 Hz, 1H), 2.21 (s, 2H), 2.10 (d, J=10.6Hz, 2H), 1.70 (d, J=11.4 Hz, 4H), 1.59 (s, 6H). LC-MS: m/z:(M+H)⁺=528.3. Compound I-1-2: HPLC retention time (RT)=10.78 min (HPLCconditions: gradient elution, 5% mobile phase B→50% mobile phase B), theyield of the compound was 72% (160 mg) as a white solid: ¹H NMR (400MHz, CDCl₃) δ 8.86 (s, 1H), 8.54 (s, 1H), 7.95 (t, J=7.9 Hz, 1H), 7.75(d, J=8.0 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.43 (d, J=7.6 Hz, 1H), 7.32(d, J=8.5 Hz, 2H), 5.72 (ddt, J=16.5, 10.3, 6.2 Hz, 1H), 5.06 (d, J=10.2Hz, 1H), 4.95 (dd, J=17.1, 1.0 Hz, 1H), 4.75 (d, J=6.1 Hz, 2H), 3.05 (m,1H), 2.93 (m, 1H), 2.68 (s, 6H), 2.32 (m, 2H), 1.84 (m, 6H), 1.60 (s,6H). LC-MS: m/z: (M+H)⁺=528.3.

Embodiment 3

Compound (I-3-1) and compound (I-3-2) can be synthesized by the samemethod as in embodiment 1 using cyclopentane as a raw material. Thedetails were as follows:

Step 1:

Sodium borohydride acetate (0.85 g, 4 mmol) was added to a mixture oftert-butyl (4′-oxo-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)carbamate(0.46 g, 1.6 mmol) (1-8-c) and tetrahydropyrrole (0.28 g, 3.9 mmol) in20 mL of dichloromethane, and the mixture was stirred overnight at roomtemperature; the reaction mixture was washed with saturated sodiumcarbonate aqueous solution (20 mL), water (2*10 mL) and saturated salinesequentially; the organic phase was dried over anhydrous sodium sulfate,and the residue was mixed with silica gel and passed through a column{7M ammonia methanol: (dichloromethane:ethyl acetate=12:2)=0-15%} toobtain compound I-3-a, 200 mg of white solid. The yield was 40%. LC-MS:m/z: (M+H)⁺=343.

Step 2:

Tert-butyl(4′-(pyrrolidin-1-yl)-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)carbamate(300 mg, 0.87 mmol) (I-3-a) and 10% palladium carbon (100 mg) were addedto 30 mL of methanol, the reaction flask was ventilated three times witha hydrogen balloon, and the reaction mixture was stirred overnight atroom temperature in a hydrogen atmosphere. The reaction mixture wasfiltered and evaporated to dryness to obtain a crude product, which wasseparated by thin layer chromatography silica gel plate {7M ammoniamethanol: (dichloromethane:ethyl acetate=9:3)=1:12} to obtain compoundI-3-2-b, 70 mg of white solid (Rf=0.7), and compound I-3-1-b, 90 mg ofwhite solid (Rf=0.5). The total yield was 52%. LC-MS: m/z: (M+H)⁺=345.

Step 3:

Tert-butyl (4-(4-(pyrrolidin-1-yl)cyclohexyl)phenyl)carbamate (I-3-2-b)(Rf=0.7) (70 mg, 0.2 mmol) was added to 2 mL of dichloromethane, then 2mL of trifluoroacetic acid was added thereto, and the mixture wasstirred at room temperature for 2 hours. After the reaction mixture wasconcentrated, a brown oil (I-3-2-c) was obtained, which was directlyused for the next step. LC-MS: m/z: (M+H)⁺=245.

Tert-butyl (4-(4-(pyrrolidin-1-yl)cyclohexyl)phenyl)carbamate (I-3-1-b)(Rf=0.5) (70 mg, 0.2 mmol) was added to 2 mL of dichloromethane, then 2mL of trifluoroacetic acid was added thereto, and the mixture wasstirred at room temperature for 2 hours. After the reaction mixture wasconcentrated, a brown oil (I-3-1-c) was obtained, which was directlyused for the next step. LC-MS: m/z: (M+H)⁺=245.

Step 4:

m-Chloroperoxybenzoic acid (66 mg, 0.326 mmol) was added to a solutionof2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(I-1-h) (90 mg, 0.25 mmol) in 10 mL of toluene, and the obtained mixturewas stirred at room temperature for 1 hour. The above reaction mixturewas concentrated, and then trifluoroacetate of 4-(4-(azetidin-1-yl)cyclohexyl)aniline (I-3-1-c) (0.26 mmol), 0.15 mL of trifluoroaceticacid and 3 mL of dimethyl sulfoxide were added thereto, and the mixturewas stirred at 60° C. overnight. 2 ML of saturated sodium carbonateaqueous solution and 10 mL of water were added to the above reactionmixture, and the mixture was extracted three times with dichloromethane(3*10 mL); then the organic phase was combined, washed with 5 mL ofwater and 5 mL of saturated sodium chloride solution, respectively,dried over anhydrous sodium sulfate, and concentrated to obtain a crudeproduct; the crude product was separated by thin layer chromatographyplate {7M ammonia methanol: (dichloromethane:ethyl acetate=5:1)=1:12} toobtain compound I-3-1, 40 mg of white solid (Rf=0.4), the yield was 28%.Compound 1-3-1: HPLC retention time (RT)=11.01 min (HPLC conditions:mobile phase A was water (containing 0.1% HCOOH), mobile phase B wasacetonitrile; gradient elution: 5% mobile phase B→50% mobile phase B),¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, 1H), 7.90 (t, J=7.9 Hz, 1H), 7.78 (d,J=8.0 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.39 (dd, J=7.6, 0.5 Hz, 1H),7.20 (d, J=8.5 Hz, 2H), 5.72 (ddt, J=16.4, 10.2, 6.2 Hz, 1H), 5.06 (dd,J=10.2, 1.0 Hz, 1H), 4.95 (dd, J=17.1, 1.2 Hz, 1H), 4.76 (d, J=6.2 Hz,2H), 4.04 (s, 1H), 2.66 (m, 4H), 2.58-2.47 (m, 1H), 2.16 (m, 4H), 1.96(m, 2H), 1.87-1.78 (m, 4H), 1.60 (s, 6H), 1.58-1.39 (m, 4H). LC-MS: m/z:(M+H)⁺=554.

m-Chloroperoxybenzoic acid (60 mg, 0.296 mmol) was added to a solutionof2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(I-1-h) (80 mg, 0.22 mmol) in 10 mL of toluene, and the obtained mixturewas stirred at room temperature for 1 hour. The above reaction mixturewas concentrated, and then trifluoroacetate of 4-(4-(azetidin-1-yl)cyclohexyl)aniline (I-3-2-c) (0.2 mmol), 0.15 mL of trifluoroacetic acidand 3 mL of dimethyl sulfoxide were added thereto, and the mixture wasstirred at 60° C. overnight. 2 ML of saturated sodium carbonate aqueoussolution and 10 mL of water were added to the above reaction mixture,and the mixture was extracted three times with dichloromethane (3*10mL); then the organic phase was combined, washed with 5 mL of water and5 mL of saturated sodium chloride solution, respectively, dried overanhydrous sodium sulfate, and concentrated to obtain a crude product;the crude product was separated by thin layer chromatography plate {7Mammonia methanol: (dichloromethane:ethyl acetate=5:1)=1:12} to obtaincompound I-3-2, 50 mg of white solid (Rf=0.6), the yield was 40%.Compound 1-3-2: HPLC retention time (RT)=11.20 min (HPLC conditions:mobile phase A was water (containing 0.1% HCOOH), mobile phase B wasacetonitrile; gradient elution: 5% mobile phase B→50% mobile phase B),¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, 1H), 7.92 (t, J=7.9 Hz, 1H), 7.80 (d,J=8.0 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.38 (d, J=7.6 Hz, 1H), 7.29 (t,J=4.2 Hz, 2H), 5.79-5.66 (m, 1H), 5.06 (dd, J=10.2, 1.0 Hz, 1H), 4.96(dd, J=17.1, 1.2 Hz, 1H), 4.77 (d, J=6.2 Hz, 2H), 4.02 (s, 1H),2.70-2.50 (m, 5H), 2.26 (s, 1H), 1.98 (m, 4H), 1.82 (s, 4H), 1.69-1.56(m, 10H). LC-MS: m/z: (M+H)⁺=554.

Embodiment 4

Step 1:

1-Bromo-4-nitrobenzene (I-4-a) (692 mg, 3.43 mmol), ethyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate(I-4-b) (800 mg, 2.85 mmol), tetrakis(triphenylphosphine)palladium (330mg, 0.286 mmol), triphenylphosphine (75 mg, 0.286 mmol) and potassiumcarbonate (789 mg, 5.71 mmol) were dissolved in 1,4-dioxane (20 mL), themixture was heated to 90° C. under the protection of argon and stirredfor about 16 hours. Then the reaction mixture was concentrated andpurified by column chromatography (silica gel, petroleum ether/ethylacetate=100% to 90%) to obtain 450 mg of the compound represented byformula I-4-c as a white solid. Yield: 47%. ¹H NMR (400 MHz, CDCl₃) δ8.23-8.16 (m, 2H), 7.57-7.49 (m, 2H), 6.33 (dd, J=5.1, 2.8 Hz, 1H),4.26-4.15 (m, 2H), 2.72-2.61 (m, 1H), 2.59-2.51 (m, 4H), 2.24 (ddd,J=9.3, 8.0, 3.9 Hz, 1H), 1.90 (dddd, J=13.1, 11.0, 8.8, 6.7 Hz, 1H),1.31 (dd, J=9.2, 5.1 Hz, 3H).

Step 2:

Ethyl 4-(4-nitrophenyl)cyclohex-3-ene-1-carboxylate (I-4-c) (450 mg,1.63 mmol) was dissolved in methanol (10 mL), palladium/carbon catalyst(45 mg, 10%) was added thereto, and the mixture was stirred at roomtemperature for about 2 days under hydrogen atmosphere, filtered, thefiltrate was concentrated and purified by column chromatography (silicagel, petroleum ether/ethyl acetate=100% to 90%) to obtain 280 mg of thecompound represented by formula I-4-d as a white solid. Yield: 69%.LC-MS: m/z: (M+H)⁺=248.4.

Step 3:

2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6-methylthiopyrazolo[3,4-d]pyrimidin-3-one(I-1-h) (428 mg, 1.20 mmol) was dissolved in toluene (20 mL),m-chloroperoxybenzoic acid (259 mg, 1.5 mmol) was added thereto, themixture was stirred at room temperature for about 1 hour, then ethyl4-(4-aminophenyl)cyclohexane carboxylate (247 mg, 1.0 mmol) and DIPEA(258 mg, 2.0 mmol) were added thereto, and the mixture was heated to 90°C. and stirred for about 16 hours. The reaction mixture was concentratedand purified by column chromatography (silica gel,dichloromethane/methanol=100% to 90%), preparative high performanceliquid phase, and thin layer chromatography (DCM/CH₃OH/NH₃CH₃OH=10/1/0.15) to obtain 440 mg of the compound represented by formulaI-4 as a white solid, yield: 79%. ¹H NMR (400 MHz, CDCl₃) δ 8.87 (d,J=2.1 Hz, 1H), 7.91 (td, J=7.9, 1.5 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H),7.54 (t, J=7.9 Hz, 2H), 7.39 (d, J=7.7 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H),5.72 (ddt, J=16.4, 10.2, 6.2 Hz, 1H), 5.07 (dd, J=10.2, 1.1 Hz, 1H),4.96 (dd, J=17.1, 1.2 Hz, 1H), 4.77 (d, J=6.2 Hz, 2H), 4.25-4.10 (m,2H), 3.95 (s, 1H), 2.73 (s, 1H), 2.56 (dt, J=15.5, 10.8 Hz, 1H), 2.28(d, J=7.9 Hz, 1H), 2.14 (d, J=10.6 Hz, 1H), 2.05-1.97 (m, 1H), 1.78 (dd,J=19.0, 8.5 Hz, 1H), 1.67 (dt, J=10.1, 6.1 Hz, 3H), 1.61 (s, 6H),1.59-1.44 (m, 1H), 1.34-1.26 (m, 3H). LC-MS: m/z: (M+H)⁺=557.4.

Embodiment 5

4-[4-[[2-Allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-3-oxo-pyrazolo[3,4-d]pyrimidin-6-ethyl[amino]phenyl]cyclohexanecarboxylate (I-4) (420 mg, 0.75 mmol) was dissolved in methanol (20 mL),2N sodium hydroxide aqueous solution (10 mL) was added, the mixture wasstirred at room temperature for about 3 days, concentrated to removemethanol, extracted with dichloromethane, then the organic layer wasdiscarded, and the pH value was adjusted to 4 by adding 1N hydrochloricacid aqueous solution to the aqueous layer, then the the aqueous layerwas extracted with dichloromethane; and the organic layer was dried overanhydrous sodium sulfate, concentrated, purified by columnchromatography (silica gel, dichloromethane/methanol=100% to 95%) toobtain 256 mg of the compound represented by formula I-5 as a whitesolid, yield: 64%. ¹H NMR (400 MHz, MeOD) δ 8.84 (d, J=1.4 Hz, 1H), 8.00(td, J=7.9, 4.0 Hz, 1H), 7.83-7.76 (m, 1H), 7.67 (dd, J=7.7, 0.7 Hz,1H), 7.60 (dd, J=8.4, 5.7 Hz, 2H), 7.19 (dd, J=13.2, 8.6 Hz, 2H), 5.73(ddd, J=17.0, 6.1, 4.1 Hz, 1H), 5.08-5.03 (m, 1H), 4.95 (d, J=1.3 Hz,1H), 4.86-4.79 (m, 2H), 2.72 (s, 1H), 2.58 (s, 1H), 2.27 (d, J=6.7 Hz,1H), 2.13 (d, J=10.0 Hz, 1H), 1.96 (d, J=10.2 Hz, 1H), 1.80-1.66 (m,4H), 1.64-1.52 (m, 7H). LC-MS: m/z: (M+H)⁺=529.3.

Embodiment 6

40 mg (0.076 mmol) of4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)cyclohexane-1-carboxylicacid (I-5) was dissolved in 5 mL of dichloromethane, and 9 mg (0.11 mol)of dimethylamine hydrochloride, 17 mg (0.11 mmol) of EDCI, 15 mg (0.11mmol) of HOBt and 19 mg (0.15 mmol) of DIPEA were added thereto, and themixture was stirred at room temperature for about 16 hours, and thenpurified by thin layer chromatography (DCM/CH3OH=100/10) to obtain 15 mgof a light yellow solid (I-6), the yield was 35%. ¹H NMR (400 MHz,CDCl₃) δ 8.86 (d, J=4.2 Hz, 1H), 7.97-7.88 (m, 1H), 7.79 (d, J=8.0 Hz,1H), 7.53 (dd, J=12.3, 8.5 Hz, 2H), 7.39 (d, J=7.6 Hz, 1H), 7.28-7.15(m, 2H), 5.80-5.65 (m, 1H), 5.06 (d, J=10.0 Hz, 1H), 4.95 (d, J=17.1 Hz,1H), 4.77 (d, J=6.0 Hz, 2H), 3.10 (d, J=12.1 Hz, 3H), 2.98 (s, 3H),2.67-2.57 (m, 1H), 2.14 (dd, J=20.9, 10.3 Hz, 1H), 2.06-1.97 (m, 2H),1.92 (d, J=14.0 Hz, 1H), 1.78-1.66 (m, 4H), 1.61 (s, 6H), 1.49 (dd,J=22.8, 12.2 Hz, 1H). LC-MS: m/z: (M+H)⁺=556.3.

Embodiment 7

40 mg (0.076 mmol) of4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)cyclohexane-1-carboxylicacid (I-5) was dissolved in 5 mL of dichloromethane, and 9 mg (0.11 mol)of azetidine hydrochloride (I-7-a), 17 mg (0.11 mmol) of EDCI, 15 mg(0.11 mmol) of HOBt and 19 mg (0.15 mmol) of DIPEA were added thereto,and the mixture was stirred at room temperature for about 16 hours, andthen purified by thin layer chromatography (DCM/CH3OH=100/10) to obtain15 mg of a light yellow solid (I-7), the yield was 35%. ¹H NMR (400 MHz,CDCl₃) δ 8.85 (d, J=4.7 Hz, 1H), 7.91 (dt, J=10.7, 7.9 Hz, 1H), 7.78 (d,J=7.8 Hz, 1H), 7.53 (dd, J=12.0, 8.5 Hz, 2H), 7.39 (dd, J=7.6, 2.4 Hz,1H), 7.22 (dd, J=19.5, 8.5 Hz, 2H), 5.71 (ddt, J=16.4, 10.2, 6.2 Hz,1H), 5.06 (d, J=10.2 Hz, 1H), 4.95 (d, J=17.1 Hz, 1H), 4.77 (d, J=6.1Hz, 2H), 4.21 (dd, J=16.4, 8.6 Hz, 2H), 4.10-4.02 (m, 2H), 2.63-2.52 (m,2H), 2.35-2.20 (m, 2H), 2.15-2.07 (m, 1H), 2.00 (dd, J=13.4, 3.0 Hz,2H), 1.92-1.83 (m, 1H), 1.79-1.63 (m, 4H), 1.60 (s, 6H), 1.48 (ddd,J=24.7, 12.5, 2.5 Hz, 1H). LC-MS: m/z: (M+H)⁺=568.4.

Embodiment 8

Step 1:

4,4,5,5-Tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane(I-1-c) (19 g, 71.4 mmol), tert-butyl (4-bromophenyl)carbamate (I-8-a)(18.4 g, 67.6 mmol), 2 mol/L sodium carbonate aqueous solution (75 mL)and Pd(dppf)Cl₂ (3.3 g, 4.5 mmol) were added to 250 mL of 1,4-dioxane,and the reaction flask was ventilated with a nitrogen balloon for threetimes, and the mixture was stirred at 98° C. overnight. The reactionmixture was filtered and concentrated, and the aqueous phase wasextracted with ethyl acetate (2*100 mL), the combined organic phase waswashed with saturated saline, dried over anhydrous sodium sulfate andconcentrated to obtain a crude product, which was purified by column(ethyl acetate:petroleum ether=0-40%) to obtain 19 g of a brown solid(I-8-b). The yield was 84.8%. LC-MS: m/z: (M-56+H)⁺=276.

Step 2:

1.38 Mol/L hydrochloric acid (160 mL) was added to a solution oftert-butyl (4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenyl)carbamate (I-8-b)(16 g, 48 mmol) in 100 mL of tetrahydrofuran, and the mixture wasstirred at room temperature overnight. Then the mixture was extractedwith ethyl acetate (2*150 mL), the combined organic phase was washedthree times with saturated saline, and the organic phase was dried overanhydrous sodium sulfate and concentrated to obtain 13.5 g of ayellow-brown solid (I-8-c), which was directly used for the next step.The yield was 97%. LC-MS: m/z: (M-56+H)⁺=232.

Step 3:

N,N′-diisopropylethylamine (12 mL, 69 mmol) and sodium borohydrideacetate (14 g, 71 mmol) were added to a mixture of tert-butyl(4′-oxo-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)carbamate (I-8-c)(10 g, 34.8 mmol) and azetidine hydrochloride (3 g, 32 mmol) in 100 mLof dichloromethane, and the mixture was stirred at room temperatureovernight; then the solvent was evaporated, and 100 mL ofdichloromethane was added thereto, and the mixture was washed withsaturated sodium carbonate aqueous solution (20 mL), water (2*30 mL) andsaturated saline sequentially; then the organic phase was dried overanhydrous sodium sulfate and then mixed with silica gel and passedthrough the column {7M ammonia methanol:(dichloromethane:ethylacetate=15:1)=0-15%} to obtain 7.3 g of white solid (I-8-d). The yieldwas 64%. LC-MS: m/z: (M+H)⁺=329.

Step 4:

Tert-butyl(4′-(azetidin-1-yl)-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)carbamate(I-8-d) (7.3 g, 22 mmol) and 10% palladium carbon (200 mg) were added to150 mL of methanol, the reaction flask was ventilated three times with ahydrogen balloon, and the reaction mixture was stirred overnight at roomtemperature in a hydrogen atmosphere. The reaction mixture was filteredand evaporated to dryness to obtain a crude product, the crude productwas washed with ethyl acetate and filtered, and the filter cake was 4.1g of compound I-8-e (Rf=0.4) as a white solid. The total yield was 85%.LC-MS: m/z: (M+H)⁺=331.

Step 5:

Tert-butyl (4-(4-(azetidin-1-yl)cyclohexyl)phenyl)carbamate (3 g, 9mmol) (represented by formula I-8-e) was added to 20 mL ofdichloromethane, then 20 mL of trifluoroacetic acid was added thereto,and the mixture was stirred at room temperature for 2 hours. After thereaction mixture was concentrated, 10 mL of water and 20 mL of saturatedsodium carbonate solution were added thereto, and the formed solid wasfiltered, washed with water and drained to obtain 1.8 g of compoundI-8-f as a brown solid, which was directly used in the next step. Theyield was 86%. ¹H NMR (400 MHz, CDCl₃) δ 7.08-6.96 (m, 2H), 6.70-6.60(m, 2H), 3.57 (s, 2H), 3.22 (t, J=7.0 Hz, 4H), 2.38 (tt, J=12.1, 3.2 Hz,1H), 2.15-1.95 (m, 5H), 1.95-1.81 (m, 4H), 1.51-1.30 (m, 2H), 1.21-1.04(m, 2H). LC-MS: m/z: (M+H)⁺=231.

Step 6:

m-Chloroperoxybenzoic acid (1.33 g, 6.57 mmol) was added to a solutionof2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(1.86 g, 5.2 mmol) (represented by I-1-h) in 60 mL of toluene, and theobtained mixture was stirred at room temperature for 1 hour. The abovereaction mixture was concentrated, and then4-(4-(azetidin-1-yl)cyclohexyl)aniline (1.2 g, 5.2 mmol) (represented byI-8-f), 0.8 mL of trifluoroacetic acid and 20 mL of dimethyl sulfoxidewere added thereto, and the mixture was stirred at 60° C. overnight. 20ML of saturated sodium carbonate aqueous solution and 50 mL of waterwere added to the above reaction mixture, and the mixture was extractedthree times with dichloromethane (3*150 mL); then the organic phase wascombined, washed with 50 mL of water and 30 mL of saturated sodiumchloride solution, respectively, dried over anhydrous sodium sulfate,and concentrated to obtain a crude product; the crude product wasseparated by thin layer chromatography plate {7M ammonia methanol:(dichloromethane:ethyl acetate=5:1)=1:12} to obtain compound I-8, 1.88 gof a white solid, the yield was 67%. ¹H NMR (400 MHz, CDCl₃) δ 8.86 (s,1H), 7.93-7.85 (m, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H),7.39 (dd, J=7.6, 0.7 Hz, 1H), 7.19 (d, J=8.5 Hz, 2H), 5.71 (ddt, J=16.4,10.2, 6.2 Hz, 1H), 5.05 (dd, J=10.2, 1.1 Hz, 1H), 4.94 (dd, J=17.1, 1.3Hz, 1H), 4.77 (d, J=6.2 Hz, 2H), 4.11 (d, J=8.9 Hz, 1H), 3.24 (t, J=7.0Hz, 4H), 2.52-2.43 (m, 1H), 2.14-2.00 (m, 3H), 1.92 (d, J=11.2 Hz, 4H),1.60 (s, 6H), 1.45 (dt, J=14.9, 7.5 Hz, 2H), 1.23-1.08 (m, 2H). LC-MS:m/z: (M+H)⁺=540.4.

Embodiment 8-1

The product of embodiment 8 (compound I-8) was detected by HPLC(conditions: mobile phase A was water (containing HCOOH 0.1%), mobilephase B was acetonitrile; gradient elution: 5% mobile phase B→50% mobilephase B) with the only retention time: HPLC retention time (RT)=10.78min. Therefore, its cyclohexyl part was cis or trans, i.e., it was

refers to cis or trans.

The reaction route was as follows:

Embodiment 8-2

2-Allyl-1-(6-(2-hydroxypropan)pyridin-2-yl)-6-((4-(4-oxocyclohexyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(I-19-d) (19.0 mmol) was dissolved in dichloromethane (500 mL), andazetidine hydrochloride (21.0 mmol), N-ethyl-N-isopropyl-2-amine (38.0mmol) and sodium triacetoxyborohydride (57 mmol) were added to thereaction mixture, and the reaction mixture was stirred at 30° C. for 16hours. Water (300 mL) and potassium carbonate were added to the reactionmixture, the pH value was adjusted to 9, and the mixture was extractedwith dichloromethane; the organic phase was washed with saturatedsaline, dried over anhydrous magnesium sulfate, filtered, and thefiltrate was evaporated to dryness to obtain a crude product, and thecrude product was purified by column chromatography(dichloromethane/methanol=0/100-5/95) to obtain target compound I-8-1(1.8 g, 24.7%) and target compound I-8-2 (4.7 g, 65.3%), both of whichwere white solids.

Compound I-8-1: HPLC: retention time (RT)=10.78 min (HPLC conditions:mobile phase A was water (containing HCOOH 0.1%), mobile phase B wasacetonitrile; gradient elution: 5% mobile phase B→50% mobile phase B),¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 7.93-7.85 (m, 1H), 7.78 (d,J=7.8 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.39 (dd, J=7.6, 0.7 Hz, 1H),7.19 (d, J=8.5 Hz, 2H), 5.71 (ddt, J=16.4, 10.2, 6.2 Hz, 1H), 5.05 (dd,J=10.2, 1.1 Hz, 1H), 4.94 (dd, J=17.1, 1.3 Hz, 1H), 4.77 (d, J=6.2 Hz,2H), 4.11 (d, J=8.9 Hz, 1H), 3.24 (t, J=7.0 Hz, 4H), 2.52-2.43 (m, 1H),2.14-2.00 (m, 3H), 1.92 (d, J=11.2 Hz, 4H), 1.60 (s, 6H), 1.45 (dt,J=14.9, 7.5 Hz, 2H), 1.23-1.08 (m, 2H). LC-MS: m/z: (M+H)⁺=540.4.

Compound I-8-2: HPLC: retention time (RT)=11.00 min (HPLC conditions:mobile phase A was water (containing HCOOH 0.1%), mobile phase B wasacetonitrile; gradient elution: 5% mobile phase B→50% mobile phase B),¹H NMR (400 MHz, CDCl₃) δ8.87 (s, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.80 (d,J=8.0 Hz, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.39 (d, J=7.6 Hz, 1H), 7.29-7.25(m, 2H), 5.82-5.63 (m, 1H), 5.12-4.91 (m, 2H), 4.78 (d, J=6.2 Hz, 2H),4.01 (s, 1H), 3.17 (s, 4H), 2.53 (s, 1H), 2.33 (s, 1H), 2.06 (d, J=4.4Hz, 2H), 1.89 (d, J=11.6 Hz, 2H), 1.75 (d, J=14.1 Hz, 2H), 1.59 (d,J=17.2 Hz, 8H), 1.46 (t, J=13.1 Hz, 2H). LC-MS: 540.0[M+1]⁺.

It can be seen that there was a big difference between the cis- andtrans-configuration hydrogen spectrum data, which was enough todistinguish them.

Embodiment 8-3

Step 1:

Tert-butyl(4′-(azetidin-1-yl)-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)carbamate(I-8-d) (7.3 g, 22 mmol) and 10% palladium carbon (200 mg) were added to150 mL of methanol, the reaction flask was ventilated three times with ahydrogen balloon, and the reaction mixture was stirred overnight at roomtemperature in a hydrogen atmosphere. The reaction mixture was filteredand evaporated to dryness to obtain a crude product, which was mixedwith silica gel and passed through the column {7 M ammoniamethanol:(dichloromethane:ethyl acetate=12:3)=0-15%} to obtain 2.1 g ofcompound I-8-e″ (Rf=0.6) as a white solid and 4.1 g of compound I-8-e′as a white solid (Rf=0.4). The total yield was 85%. LC-MS: m/z:(M+H)⁺=331.

Step 2:

Tert-butyl (4-(4-(azetidin-1-yl)cyclohexyl)phenyl)carbamate (2 g, 9mmol) (represented by formula I-8-e″) was added to 20 mL ofdichloromethane, then 20 mL of trifluoroacetic acid was added thereto,and the mixture was stirred at room temperature for 2 hours. After thereaction mixture was concentrated, 10 mL of water and 20 mL of saturatedsodium carbonate solution were added thereto, and the formed solid wasfiltered, washed with water and drained to obtain 1.2 g of compoundI-8-f″ as a brown solid, which was directly used in the next step. Theyield was 86%. ¹H NMR (400 MHz, MeOD) δ 7.10-6.97 (m, 2H), 6.74-6.63 (m,2H), 4.22-4.08 (t, J=8.0 Hz, 4H), 3.47-3.38 (m, 1H), 2.61-2.52 (m, 1H),2.52-2.28 (m, 2H), 1.92-1.62 (m, 8H). LC-MS: m/z: (M+H)⁺=231.

Step 3:

m-Chloroperoxybenzoic acid (1.33 g, 6.57 mmol) was added to a solutionof2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(1.86 g, 5.2 mmol) (represented by I-1-h) in 60 mL of toluene, and theobtained mixture was stirred at room temperature for 1 hour. The abovereaction mixture was concentrated, and then4-(4-(azetidin-1-yl)cyclohexyl)aniline (1.2 g, 5.2 mmol) (represented byI-8-f″), 0.8 mL of trifluoroacetic acid and 20 mL of dimethyl sulfoxidewere added thereto, and the mixture was stirred at 60° C. overnight. 20ML of saturated sodium carbonate aqueous solution and 50 mL of waterwere added to the above reaction mixture, and the mixture was extractedthree times with dichloromethane (3*150 mL); then the organic phase wascombined, washed with 50 mL of water and 30 mL of saturated sodiumchloride solution, respectively, dried over anhydrous sodium sulfate,and concentrated to obtain a crude product; the crude product wasseparated by thin layer chromatography plate {7M ammonia methanol:(dichloromethane:ethyl acetate=5:1)=1:12} to obtain compound I-8-2, 1.88g of a white solid, the yield was 67%. ¹H NMR (400 MHz, CDCl₃) δ8.87 (s,1H), 7.92 (d, J=7.8 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.4 Hz,2H), 7.39 (d, J=7.6 Hz, 1H), 7.29-7.25 (m, 2H), 5.82-5.63 (m, 1H),5.12-4.91 (m, 2H), 4.78 (d, J=6.2 Hz, 2H), 4.01 (s, 1H), 3.17 (s, 4H),2.53 (s, 1H), 2.33 (s, 1H), 2.06 (d, J=4.4 Hz, 2H), 1.89 (d, J=11.6 Hz,2H), 1.75 (d, J=14.1 Hz, 2H), 1.59 (d, J=17.2 Hz, 8H), 1.46 (t, J=13.1Hz, 2H). LC-MS: m/z: (M+H)⁺=540.

Embodiment 15

Step 1:

1 g (4.22 mmol) of 2,6-dibromopyridine (I-15-a) was dissolved in 30 mLof dichloromethane, the mixture was cooled to −78° C., and 1.86 mL (4.64mmol, 2M solution of dioxane) of n-butyllithium solution was slowlyadded dropwise, after the mixture was stirred for about 15 min, and 0.3g (4.22 mmol) of oxetan-3-one (represented by formula I-15-b) was addedthereto, the stirring was continued for about 1 hour; and the mixturewas quenched with saturated ammonium chloride aqueous solution, and thenextracted with dichloromethane, the organic layer was dried overanhydrous sodium sulfate, concentrated, and purified by columnchromatography (petroleum ether/ethyl acetate=100% to 50%) to obtain 660mg of 3-(6-bromo-2-pyridyl)oxetan-3-ol (I-15-c) as a white solid, theyield was 68%. LC-MS: m/z: (M+H)⁺=230.1.

Step 2:

106 mg (0.48 mmol) of2-allyl-6-methylthio-1H-pyrazolo[3,4-d]pyrimidin-3-one (I-15-d) and 100mg (0.43 mmol) of 3-(6-bromo-2-pyridyl)oxetan-3-ol (I-15-c) weredissolved into 10 mL of 1,4-dioxane, and then 90 mg (0.65 mmol) ofpotassium carbonate, 83 mg (0.43 mmol) of cuprous iodide and 77 mg (0.87mmol) of N1,N2-dimethylethyl-1,2-diamine were added thereto, and themixture was heated to 100° C. under the protection of argon and stirredovernight. The residue was concentrated and purified by silica gelcolumn chromatography (UV, dichloromethane/methanol=100% to 10%) toobtain 140 mg of2-allyl-1-[6-(3-hydroxyoxetan-3-yl)-2-pyridinyl]-6-methylthiopyrazolo[3,4-d]pyrimidin-3-one(I-15-e) as a brown oil, the yield was 86%. LC-MS: m/z: (M+H)⁺=372.1.

Step 3:

549 mg (1.478 mmol) of2-allyl-1-[6-(3-hydroxyoxetan-3-yl)-2-pyridinyl]-6-methylthiopyrazolo[3,4-d]pyrimidin-3-one(represented by I-15-e) was dissolved in 30 mL of toluene, 397 mg(1.7714 mmol) of 3-chloroperoxybenzoic acid was added thereto, and themixture was stirred at room temperature for about 1 hour, then 354 mg(1.622 mmol) of 4-(4-(dimethylamino)cyclohexyl)aniline (I-1-f) and 381mg (2.9480 mmol) of DIPEA were added thereto, and the reaction mixturewas concentrated and purified by thin layer chromatography(dichloromethane/methanol/methanol solution of ammonia=25/1/0.15) toobtain compound I-15-1 and compound I-15-2. Compound I-15-1: HPLCretention time (RT)=7.02 min (HPLC conditions: gradient elution, 5%mobile phase B→95% mobile phase B), the yield of the compound was 10%(80 mg) as a white solid; ¹H NMR (400 MHz, MeOD) δ 8.84 (s, 1H), 8.04(t, J=7.9 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.60(d, J=8.6 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 5.78 (ddt, J=16.3, 10.3, 6.1Hz, 1H), 5.12-5.05 (m, 3H), 4.98 (dd, J=17.1, 1.3 Hz, 1H), 4.89 (d,J=6.1 Hz, 2H), 4.84 (s, 2H), 3.68 (s, 2H), 2.97-2.86 (m, 1H), 2.66 (s,6H), 2.60-2.50 (m, 1H), 2.15 (d, J=8.6 Hz, 2H), 2.04 (d, J=9.0 Hz, 2H),1.66-1.54 (m, 4H). LC-MS: m/z: (M+H)⁺=542.4. Compound I-15-2: HPLCretention time (RT)=7.16 min (HPLC conditions: gradient elution, 5%mobile phase B→95% mobile phase B), the yield of the compound was 20%(160 mg) as a white solid: ¹H NMR (400 MHz, MeOD) δ 8.83 (s, 1H), 8.04(t, J=7.9 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.67-7.62 (m, 1H), 7.59 (d,J=8.6 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 5.76 (ddt, J=16.3, 10.2, 6.1 Hz,1H), 5.10-5.02 (m, 3H), 4.96 (dd, J=17.1, 1.3 Hz, 1H), 4.87 (d, J=6.8Hz, 2H), 4.82 (d, J=6.8 Hz, 2H), 2.73 (d, J=4.2 Hz, 1H), 2.29 (d, J=21.9Hz, 7H), 2.04-1.90 (m, 4H), 1.66 (dd, J=15.6, 6.1 Hz, 4H). LC-MS: m/z:(M+H)⁺=542.3.

Embodiment 19

Step 1:

4,4,5,5-Tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane(0.8 g, 3 mmol) (represented by formula I-1-c), 1-bromo-4-nitrobenzene(0.606 g, 3 mmol) (I-4-a), 1 mol/L sodium carbonate aqueous solution (6mL) and Pd(PPh₃)₂Cl₂ (106 mg, 0.15 mmol) were added to 30 mL of1,4-dioxane, and the reaction flask was ventilated three times with anitrogen balloon, and the mixture was stirred at 95° C. overnight. Thereaction mixture was filtered and concentrated, and the aqueous phasewas extracted with ethyl acetate (2×30 mL), the combined organic phasewas washed with saturated saline, dried over anhydrous sodium sulfateand concentrated to obtain a crude product, which was purified by column(ethyl acetate:petroleum ether=0-30%) to obtain 0.73 g of8-(4-nitrophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (I-19-a) as a brownsolid, the yield was 90%. ¹H NMR (400 MHz, CDCl3) δ 8.24-8.14 (m, 2H),7.60-7.50 (m, 2H), 6.21 (td, J=4.0, 2.0 Hz, 1H), 4.06 (s, 4H), 2.71(ddd, J=6.5, 4.2, 1.7 Hz, 2H), 2.59-2.49 (m, 2H), 1.97 (t, J=6.5 Hz,2H). LC-MS: m/z: (M+H)⁺=262.3.

Step 2:

8-(4-Nitrophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (I-19-a) and 10%palladium carbon (100 mg) were added to 50 mL of dichloromethane, thereaction flask was ventilated three times with a hydrogen balloon, andthe reaction mixture was stirred at room temperature for 4 hours in ahydrogen atmosphere. The reaction mixture was filtered and evaporated todryness to obtain 560 mg of 4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline(I-19-b) as a brown solid, which was directly used in the next step, theyield was 96%. LC-MS: m/z: (M+H)⁺=234.3.

Step 3:

m-Chloroperoxybenzoic acid (55 mg, 0.246 mmol) was added to a solutionof2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(72 mg, 0.2 mmol) (I-1-h) in 15 mL of toluene, and the obtained mixturewas stirred at room temperature for 1 hour. The above reaction mixturewas concentrated, and then 4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline(I-19-b), 0.15 mL of trifluoroacetic acid and 3 mL of dimethyl sulfoxidewere added thereto, and the mixture was stirred at 60° C. overnight. 10ML of saturated sodium carbonate aqueous solution and 25 mL of waterwere added to the above reaction mixture, and the mixture was extractedthree times with dichloromethane (3×20 mL); then the organic phase wascombined, washed with 10 mL of water and 10 mL of saturated sodiumchloride solution, respectively, dried over anhydrous sodium sulfate,and concentrated to obtain a crude product; the crude product wasseparated by thin layer chromatography plate {7M ammonia methanol:(dichloromethane:ethyl acetate=5:1)=1:12} to obtain 60 mg of6-((4-(1,4-dioxaspiro[4.5]decan-8-yl)phenyl)amino)-2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(represented by I-19-c) as a white solid, the yield was 54%. LC-MS: m/z:(M+H)⁺=543.3.

Step 4:

6-((4-(1,4-Dioxaspiro[4.5]decan-8-yl)phenyl)amino)-2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(represented by I-19-c) was added to a mixed solution consisting of 3 mLof tetrahydrofuran and 3 mL of 2 mol/L hydrochloric acid, and themixture was stirred at room temperature overnight. The pH of thereaction mixture was adjusted to about 10 with sodium bicarbonate,extracted with dichloromethane (2×20 mL), and the crude product wasconcentrated after the organic phase was dried over anhydrous sodiumsulfate. The obtained crude product was separated by thin layerchromatography plate with methanol:(dichloromethane:ethylacetate=9:3)=1:12 to obtain 50 mg of2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-oxocyclohexyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(I-19-d) as a white solid, the yield was 90%. LC-MS: m/z: (M+H)⁺=499.3.

Step 5:

2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-oxocyclohexyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(50 mg, 0.1 mmol) (I-19-d) and ammonium acetate (77 mg, 1 mmol) wereadded to 10 mL of methanol, the mixture was stirred at room temperaturefor 10 min, then sodium cyanoborohydride (30 mg, 0.5 mmol) was addedthereto, and the mixture was stirred overnight at room temperature.After the reaction mixture was concentrated, 20 mL of dichloromethanewas added thereto, and the mixture was washed with 10 mL of 1 mol/Lsodium carbonate solution and 5 mL of water sequentially. The organicphase was dried over anhydrous sodium sulfate, and the obtained crudeproduct was concentrated and directly used in the next step. 40 Mg ofwhite solid (I-19-e), the yield was 80%. LC-MS: m/z: (M+H)⁺=500.3.

Step 6:

2-Allyl-6-((4-(4-aminocyclohexyl)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(35 mg, 0.07 mmol) (I-19-e) and N,N-diisopropylethylamine (0.02 mL) wereadded to 10 mL of dichloromethane, then methanesulfonyl chloride (9 mg,0.078 mmol) was added thereto, and the mixture was stirred overnight atroom temperature. The reaction mixture was concentrated and thenprepared by high performance liquid phase to obtain 9 mg ofN-(4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)cyclohexyl)methanesulfonamide(I-19) as a white solid, the yield was 22%. ¹H NMR (400 MHz, CDCl₃) δ8.88 (s, 1H), 7.91 (t, J=7.9 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.56 (d,J=8.5 Hz, 2H), 7.40 (d, J=7.4 Hz, 1H), 7.19 (d, J=8.5 Hz, 2H), 5.78-5.66(m, 1H), 5.07 (dd, J=10.2, 1.0 Hz, 1H), 4.96 (dd, J=17.1, 1.2 Hz, 1H),4.77 (d, J=6.2 Hz, 2H), 4.42 (d, J=7.6 Hz, 1H), 3.49-3.35 (m, 1H), 3.04(s, 3H), 2.57-2.46 (m, 1H), 2.29-2.17 (m, 2H), 2.05-1.96 (m, 8H),1.56-1.65 (m, 2H), 1.41-1.50 (m, 2H). LC-MS: m/z: (M+H)⁺=578.3.

Embodiment 20

2-Allyl-6-((4-(4-aminocyclohexyl)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(120 mg, 0.24 mmol) (compound represented by I-19-c),1H-pyrazole-carboximidamide hydrochloride (45 mg, 0.31 mmol) andN,N-diisopropylethylamine (0.2 mL) were added to 5 mL ofN,N-dimethylformamide, the mixture was stirred at 65° C. overnight. Thereaction mixture was concentrated and separated by thin layerchromatography plate (7M ammonia methanol:dichloromethane=1:8) to obtain30 mg of white solid (compound represented by I-20), the yield was 23%.LC-MS: m/z: (M+H)⁺=542. ¹H NMR (400 MHz, MeOD) δ 8.84 (s, 1H), 8.02 (m,1H), 7.80 (m, 1H), 7.72-7.58 (m, 3H), 7.25 (m, 2H), 5.73 (ddt, J=16.5,10.3, 6.1 Hz, 1H), 5.05 (dd, J=10.2, 1.0 Hz, 1H), 4.95 (d, 1H), 4.83 (d,J=6.1 Hz, 2H), 3.54-3.42 (m, 1H), 2.59 (m, 1H), 2.14 (m, 1H), 1.98 (m,2H), 1.83 (m, 1H), 1.68 (m, 2H), 1.60 (s, 6H), 1.50 (m, 2H).

Embodiment 23

Potassium tert-butoxide (2 equiv., 0.2006 mmol) was dissolved in drydimethyl sulfoxide (1 mL, 100 mass %), and then a solution oftosylmethyl isocyanide (1.5 equiv., 0.1504 mmol) in dry dimethylsulfoxide (1 mL) was added thereto at room temperature. Compound(I-19-d) (50 mg, 0.1003 mmol) was dissolved in dry methanol (0.5 mL),the solution was added to the above reaction mixture, and then thereaction was stirred at room temperature for 12 hours. The reaction wasquenched with water, and extracted with ethyl acetate (2×20 mL), the theorganic phase was washed with saline (1×20 mL), dried over Na₂SO₄,filtered and concentrated to obtain a crude product. The crude productwas refined by normal phase silica gel column (elution conditions:dichloromethane/methanol system, methanol concentration from 0% to 10%,12 column volumes) to obtain compound (I-23): (15 mg, 0.02943 mmol), theyield was 29.35%, yellow solid. ¹H NMR (400 MHz, DMSO) δ 10.28 (s, 1H),8.88 (d, J=1.8 Hz, 1H), 8.09-7.97 (m, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.66(dd, J=20.6, 8.5 Hz, 3H), 7.19 (dd, J=11.1, 8.7 Hz, 2H), 5.74-5.61 (m,1H), 5.00 (d, J=10.2 Hz, 1H), 4.82 (d, J=17.1 Hz, 1H), 4.69 (d, J=5.5Hz, 2H), 3.23 (s, 1H), 2.74 (t, J=12.1 Hz, 1H), 2.53 (s, 1H), 2.12 (d,J=10.1 Hz, 1H), 1.98 (d, J=13.2 Hz, 1H), 1.82 (d, J=13.2 Hz, 2H),1.77-1.57 (m, 3H), 1.49 (d, J=18.2 Hz, 6H). LC-MS: m/z: (M+H)⁺=510.2.

Embodiment 31

Step 1:

3-(4-Bromophenyl)cyclobutanone (I-31-a) (4.40 mmol) was dissolved indichloromethane (10 mL); triethylamine (8.9 mmol), dimethylaminehydrochloride (8.9 mmol) and sodium triacetoxyborohydride (8.9 mmol)were added to the reaction mixture, and the reaction mixture was stirredat room temperature for 16 hours. The pH value of the reaction mixturewas adjusted to 9 with potassium carbonate aqueous solution, the mixturewas extracted with dichloromethane, the organic phase was washed withsaturated saline, dried over anhydrous sodium sulfate, filtered, and thefiltrate was evaporated to dryness to obtain 1.1 g of the crude targetcompound 3-(4-bromophenyl)-N,N-dimethylcyclobutylamine (represented byI-31-b) as a colorless oil, the yield was 97%. LC-MS: m/z: (M+H)⁺=255.4.

Step 2:

3-(4-Bromophenyl)-N,N-dimethylcyclobutylamine (I-31-b) (4.30 mmol) wasdissolved in toluene (20 mL); and diphenylmethylamine (I-31-c) (4.8mmol), sodium tert-butoxide (6.9 mmol),1,1′-binaphthyl-2,2′-bis(diphenylphosphine) (0.43 mmol) andtris(dibenzylideneacetone)dipalladium (0.13 mmol) were added to thereaction mixture, then the reaction was heated to 90° C. and stirred for16 hours under the protection of nitrogen. The reaction mixture wascooled to room temperature, and concentrated to obtain a crude product,and the crude product was purified by column chromatography(dichloromethane/methanol=100/0-95/5) to obtain 1.5 g of target compound3-(4-((diphenylmethylene)amino)phenyl)-N,N-dimethylcyclobutanamine(I-31-d) as a colorless oil, the yield was 98%. LC-MS: m/z:(M+H)⁺=355.3.

Step 3:

4-(3-Dimethylamino)cyclobutyl)aniline (I-31-d) (4.2 mmol) was dissolvedin methanol (20 mL), sodium acetate (13.0 mmol) and hydroxylaminehydrochloride (8.5 mmol) were added to the reaction mixture, and thereaction mixture was stirred at 50° C. for 16 hours. The reactionmixture was evaporated to dryness to obtain a crude product, and thecrude product was purified by column chromatography(dichloromethane/methanol=100/0-95/5) to obtain 0.75 g of the targetcompound 4-(3-dimethylamino)cyclobutyl) aniline (I-31-e), the yield was93%. LC-MS: m/z: (M+H)⁺=191.3.

Step 4:

2-Allyl-1-(7-hydroxy-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(I-1-h) (0.65 mmol) was dissolved in toluene (20 mL), and3-chloroperoxybenzoic acid (0.62 mmol) was added thereto, and thereaction mixture was stirred for 0.5 hours at room temperature.4-(3-Dimethylamino)cyclobutyl)aniline (I-31-e)(0.67 mmol) was added tothe reaction mixture, and the reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was evaporated to drynessto obtain a crude product, the crude product was slurried with ethylacetate and dichloromethane to obtain 92 mg of target compound2-allyl-6-((4-(3-(dimethylamino)cyclobutyl)phenyl)amino)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(I-31) as a white solid, the yield was 32.9%. ¹H NMR (400 MHz, DMSO) δ10.27 (s, 1H), 8.89 (s, 1H), 8.12 (s, 1H), 7.74 (dd, J=22.6, 8.3 Hz,3H), 7.64 (d, J=7.3 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 5.76-5.61 (m, 1H),5.34 (s, 1H), 5.01 (dd, J=10.3, 1.2 Hz, 1H), 4.84 (d, J=17.1 Hz, 1H),4.70 (d, J=5.7 Hz, 2H), 3.62 (s, 1H), 3.12 (s, 1H), 2.71-2.58 (m, 8H),2.38 (d, J=9.2 Hz, 2H), 1.47 (s, 6H), 1.32-1.24 (m, 1H). LC-MS: m/z:(M+H)⁺=500.3.

Embodiment 32

Compound (I-19-d) (80 mg, 0.1604 mmol, 100 mass %) was dissolved inethanol (4 mL, 100 mass %), then water (2 mL, 100 mass %) andhydroxylamine hydrochloride (3 equiv., 0.4813 mmol, 100 mass %) wereadded at room temperature, and the reaction was stirred at 70° C. for 12hours. The reaction was quenched with aq. NaHCO₃ and extracted withethyl acetate (2×20 mL), the organic phase was washed with saline (1×20mL), dried over Na₂SO₄, filtered and concentrated to obtain a crudeproduct. The crude product was washed with 2 mL of methanol and filteredto obtain compound (I-32) (60 mg, 0.1137 mmol), the yield was 70.88%,white solid. ¹H NMR (400 MHz, DMSO) δ 10.26 (s, 1H), 8.88 (s, 1H), 8.07(t, J=7.8 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.65 (dd, J=14.5, 7.9 Hz,2H), 7.22 (d, J=8.5 Hz, 2H), 5.74-5.60 (m, 1H), 5.35 (s, 1H), 5.00 (d,J=10.3 Hz, 1H), 4.83 (d, J=17.1 Hz, 1H), 4.69 (d, J=5.6 Hz, 2H), 3.74(s, 3H), 3.24-3.15 (m, 1H), 2.77 (t, J=12.0 Hz, 1H), 2.37 (d, J=14.0 Hz,1H), 2.25 (td, J=13.4, 4.6 Hz, 1H), 1.99-1.84 (m, 3H), 1.67-1.50 (m,2H), 1.49 (d, J=14.0 Hz, 6H). LC-MS: m/z: (M+H)⁺=528.

Embodiment 33

Step 1:

Compound (I-15-c) (400 mg, 1.077 mmol) was dissolved in toluene (20 mL),then m-CPBA (1.2 equiv., 1.292 mmol, 77 mass %) was added thereto atroom temperature, and the reaction was stirred for 2 hours at roomtemperature. Compound (I-33-a) (1.2 equiv., 1.292 mmol) and DIPEA (2equiv., 2.154 mmol) were added to the above reaction mixturesequentially, and the reaction was continued with stirring at roomtemperature for 12 hours. The reaction was quenched with water, andextracted with ethyl acetate (2×20 mL), the the organic phase was washedwith saline (1×20 mL), dried over Na₂SO₄, filtered and concentrated toobtain a crude product. The crude product was refined by normal phasesilica gel column (elution conditions: ethyl acetate/dichloromethanesystem, ethyl acetate concentration from 0% to 10%, 24 column volumes)to obtain compound (I-33-b): (120 mg, 0.2341 mmol), the yield was21.74%, yellow solid. ¹H NMR (400 MHz, DMSO) δ 8.91 (d, J=2.4 Hz, 1H),8.11 (t, J=7.9 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.68 (d, J=8.2 Hz, 2H),7.57 (d, J=7.7 Hz, 1H), 7.28 (d, J=8.6 Hz, 2H), 5.72 (ddd, J=23.0, 10.3,5.9 Hz, 1H), 5.02 (dd, J=10.3, 1.3 Hz, 1H), 4.95-4.89 (m, 2H), 4.87 (d,J=1.4 Hz, 1H), 4.75 (d, J=5.8 Hz, 1H), 4.70 (t, J=6.2 Hz, 2H), 3.04 (t,J=11.9 Hz, 1H), 2.67-2.53 (m, 2H), 2.30 (t, J=15.0 Hz, 2H), 2.08 (d,J=10.0 Hz, 2H), 1.96-1.81 (m, 2H).

Step 2:

Compound (I-33-b) (100 mg, 0.1951 mmol) was dissolved in methanol (3mL); and DIPEA (5 equiv., 0.9754 mmol) was added thereto, and thereaction was stirred for 5 min at room temperature. Then, Na(OAc)₃BH (3equiv., 0.5853 mmol) was added, and the reaction was continued withstirring at room temperature for 12 hours. The reaction was quenchedwith aq. NaHCO₃, and extracted with ethyl acetate (2×20 mL), the theorganic phase was washed with saline (1×20 mL), dried over Na₂SO₄,filtered and concentrated to obtain a crude product. The crude productwas refined by normal phase silica gel column (elution conditions:dichloromethane/methanol (1% ammonia methanol) system, methanolconcentration from 0% to 10%, 12 column volumes) to obtain compound(I-33): (80 mg, 0.15 mmol), the yield was 77.3%, white solid. ¹H NMR(400 MHz, MeOD) δ 8.86 (s, 0H), 8.11-8.01 (m, 1H), 7.94 (d, J=7.9 Hz,2H), 7.67 (d, J=7.6 Hz, 2H), 7.62 (d, J=8.6 Hz, 2H), 7.28 (d, J=8.5 Hz,2H), 5.83-5.74 (m, 1H), 5.09 (dd, J=7.9, 4.4 Hz, 3H), 4.98 (dd, J=17.1,1.3 Hz, 2H), 4.85 (d, J=6.7 Hz, 2H), 2.87 (s, 1H), 2.64 (s, 1H), 2.47(s, 3H), 1.97-1.67 (m, 8H). LC-MS: m/z: (M+H)⁺=529.2.

Embodiment 34

Compound (I-33) (40 mg, 0.07582 mmol), cyclopropylacetic acid (1.1 eq.,73 mg) were dissolved in dichloromethane (2 mL), then DIPEA (2 equiv.,0.1516 mmol) and HATU (1 equiv., 0.07582 mmol) were added sequentially,and the reaction was stirred for 6 hours at room temperature. Thereaction was quenched with water, and extracted with dichloromethane(2×20 mL), the the organic phase was washed with saline (1×20 mL), driedover Na₂SO₄, filtered and concentrated to obtain a crude product. Thecrude product was refined by normal phase silica gel column (elutionconditions: dichloromethane/methanol system, methanol concentration from0% to 10%, 12 column volumes) to obtain compound (I-34): (10 mg, 0.01679mmol), the yield was 22.14%, yellow solid. ¹H NMR (400 MHz, MeOD) δ 8.87(d, J=6.6 Hz, 1H), 8.06 (t, J=7.9 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.68(dd, J=7.8, 5.4 Hz, 2H), 7.61 (d, J=8.6 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H),7.24 (t, J=8.7 Hz, 1H), 5.84-5.72 (m, 1H), 5.09 (d, J=6.2 Hz, 2H), 5.07(d, J=1.3 Hz, 1H), 5.02-4.94 (m, 2H), 4.90 (s, 2H), 4.84 (d, J=6.7 Hz,2H), 3.15 (d, J=2.6 Hz, 1H), 3.08 (s, 1H), 2.95 (s, 1H), 2.71 (s, 1H),2.43 (s, 1H), 1.93-2.03 (m, 3H), 1.76 (s, 2H), 1.51 (s, 1H), 1.31 (d,J=4.3 Hz, 3H), 0.89 (dd, J=20.1, 9.0 Hz, 4H). LC-MS: m/z: (M+H)⁺=596.2.

Embodiment 35

Step 1:

Compound (I-35-a) (100 mg, 0.3444 mmol) was dissolved in tetrahydrofuran(5 mL), and TEA (5 equiv., 1.722 mmol) and compound (I-35-b) (2 equiv.,0.6887 mmol) were added, and the reaction was stirred for 8 hours atroom temperature. The reaction was quenched with water, and extractedwith ethyl acetate (2×20 mL), the the organic phase was washed withsaline (1×20 mL), dried over Na₂SO₄, filtered and concentrated to obtaina crude product. The crude product was refined by normal phase silicagel column (elution conditions: petroleum ether/ethyl acetate system,ethyl acetate concentration from 10% to 60%, 12 column volumes) toobtain compound (I-35-c): (100 mg, 0.2532 mmol), the yield was 73.54%,white solid. LC-MS: m/z: (M+H-tBu)⁺=339.1.

Step 2:

Compound (I-35-c) (200 mg, 0.5065 mmol) was dissolved in tetrahydrofuran(5 mL), then sodium hydride (2 equiv., 1.013 mmol, 60 mass %) was addedthereto, and the reaction was stirred for 2 hours at 50° C. The reactionwas quenched with water, and extracted with ethyl acetate (2×20 mL), thethe organic phase was washed with saline (1×20 mL), dried over Na₂SO₄,filtered and concentrated to obtain compound (I-35-d): (180 mg, 0.502mmol), the yield was 99.14%, white solid. ¹H NMR (400 MHz, MeOD) δ7.31(dt, J=11.6, 8.5 Hz, 3H), 7.15 (d, J=8.5 Hz, 1H), 4.07-3.92 (m, 1H),3.47 (dt, J=29.5, 7.2 Hz, 2H), 2.39 (dt, J=16.3, 8.1 Hz, 2H), 2.22 (d,J=10.1 Hz, 1H), 2.03 (s, 4H), 1.84-1.57 (m, 6H), 1.53 (d, J=2.8 Hz, 9H).LC-MS: m/z: (M+H)⁺=359.1.

Step 3:

Compound (I-35-d) (180 mg, 0.669 mmol) was dissolved in dichloromethane(4 mL), then trifluoroacetic acid (1 mL) was added thereto, and thereaction was stirred for 12 hours at room temperature. After thereaction mixture was concentrated, aq. NaHCO₃ was added thereto, and themixture was extracted with ethyl acetate (2×20 mL); the organic phasewas washed with saline (1×20 mL), dried over Na₂SO₄, filtered andconcentrated to obtain compound (I-35-e): (120 mg, 0.464 mmol), theyield was 100%, yellow solid. LC-MS: m/z: (M+H)⁺=259.1.

Step 4:

Compound (I-15-c) (100 mg, 0.2693 mmol) was dissolved in toluene (2 mL),then m-CPBA (1.2 equiv., 0.3231 mmol, 77 mass %) was added thereto atroom temperature, and the reaction was stirred for 2 hours at roomtemperature. Compound (I-35-e) (1.2 equiv., 0.3231 mmol) and DIPEA (2equiv., 0.5385 mmol) were added to the above reaction mixture at roomtemperature sequentially, and the reaction was continued with stirringat room temperature for 12 hours. The reaction was quenched with water,and extracted with ethyl acetate (2×20 mL), the the organic phase waswashed with saline (1×20 mL), dried over Na₂SO₄, filtered andconcentrated to obtain a crude product. The crude product was refined bynormal phase silica gel column (elution conditions:dichloromethane/tetrahydrofuran system, tetrahydrofuran concentrationfrom 0% to 30%, 12 column volumes) to obtain compound (I-35): (40 mg,0.06876 mmol), the yield was 25.54%, white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.87-8.79 (m, 1H), 8.14-8.07 (m, 1H), 8.04-7.96 (m, 1H),7.89-7.80 (m, 1H), 7.61-7.50 (m, 2H), 7.38-7.32 (m, 1H), 7.25-7.19 (m,1H), 7.01 (t, J=3.4 Hz, 1H), 5.72 (ddd, J=16.6, 11.1, 8.6 Hz, 1H),5.17-5.09 (m, 2H), 5.04-4.98 (m, 1H), 4.98-4.92 (m, 1H), 4.87-4.77 (m,2H), 4.73-4.64 (m, 2H), 4.20-4.06 (m, 1H), 3.47-3.38 (m, 1H), 3.38-3.29(m, 1H), 3.05-2.98 (m, 1H), 2.49-2.35 (m, 2H), 2.27-2.17 (m, 1H),2.07-1.86 (m, 4H), 1.75-1.60 (m, 3H). LC-MS: m/z: (M+H)⁺=582.2.

Embodiment 36

2-Allyl-1-(6-(3-hydroxyoxetan-3-yl)pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(represented by formula 1-15-c) (200 mg, 0.538 mmol) was dissolved in 5mL of toluene, and 3-chloroperoxybenzoic acid (140 mg, 0.69 mmol) wasadded thereto, and the reaction mixture was stirred at 20° C. for 2hours. The reaction mixture was concentrated to dryness under reducedpressure. The obtained solid was dissolved in 5 mL of DMSO, andtrifluoroacetic acid (20 mg, 0.2 mmol) and4-(4-(azetidin-1-yl)cyclohexyl)aniline (represented by formula I-36-a)(140 mg, 0.64 mmol) were added, and the reaction mixture was stirred at65° C. for 16 hours. The reaction was quenched with water and thenextracted with dichloromethane (30 mL*3), the organic layer was driedover anhydrous sodium sulfate, concentrated and purified by columnchromatography (methanol/dichloromethane/ethyl acetate=0.5:10:4 to1:10:4) to obtain a yellow solid (I-36-2) (22 mg, 7.4%) and a yellowsolid (I-36-1) (64 mg, 21.4%). Compound I-36-1: HPLC retention time(RT)=7.14 min (HPLC conditions: mobile phase A was water (containingHCOOH 0.1%), mobile phase B was acetonitrile; gradient elution: 5%mobile phase B→95% mobile phase B), ¹H NMR (400 MHz, CDCl₃) δ8.88 (d,J=2.6 Hz, 1H), 8.09 (dd, J=15.0, 7.8 Hz, 1H), 7.99-7.83 (m, 2H), 7.54(t, J=9.5 Hz, 2H), 7.39 (d, J=8.7 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 5.74(dq, J=10.5, 5.9 Hz, 1H), 5.12 (t, J=8.8 Hz, 3H), 4.99 (d, J=17.1 Hz,1H), 4.80 (d, J=6.3 Hz, 2H), 4.67 (d, J=6.0 Hz, 2H), 3.39-3.24 (m, 4H),2.60-2.34 (m, 3H), 2.14 (dt, J=14.0, 6.8 Hz, 3H), 1.96 (d, J=10.8 Hz,4H), 1.55-1.37 (m, 2H), 1.27-1.12 (m, 2H); LC-MS: m/z: (M+H)⁺=554.1.Compound I-36-2: HPLC retention time (RT)=7.15 min (HPLC conditions:mobile phase A was water (containing HCOOH 0.1%), mobile phase B wasacetonitrile; gradient elution: 5% mobile phase B→95% mobile phase B),¹H NMR (400 MHz, MeOD) δ8.86 (s, 1H), 8.02 (dt, J=24.0, 7.9 Hz, 3H),7.64 (dd, J=27.1, 8.1 Hz, 3H), 7.27 (t, J=8.6 Hz, 2H), 7.01-6.91 (m,3H), 6.72-6.64 (m, 3H), 5.79 (ddd, J=16.3, 11.2, 6.1 Hz, 1H), 5.10-5.05(m, 2H), 4.85 (d, J=6.8 Hz, 2H), 2.57 (d, J=10.7 Hz, 1H), 2.48-2.28 (m,3H), 2.23-2.06 (m, 3H), 1.98-1.71 (m, 6H), 1.58 (dd, J=23.2, 12.9 Hz,3H), 1.44 (ddd, J=16.1, 13.2, 3.5 Hz, 2H), 1.19-1.00 (m, 2H); LC-MS:m/z: (M+H)⁺=554.1.

Embodiment 37

Step 1:

Compound (I-35-a) (150 mg, 0.5165 mmol) was dissolved in tetrahydrofuran(6 mL), and DIPEA (5 equiv., 2.583 mmol) and compound (I-35-a) (3equiv., 1.550 mmol) were added thereto, and the reaction was stirred for12 hours at room temperature. The reaction was quenched with water, andextracted with ethyl acetate (2×20 mL), the the organic phase was washedwith saline (1×20 mL), dried over Na₂SO₄, filtered and concentrated toobtain a crude product. The crude product was refined by normal phasesilica gel column (elution conditions: petroleum ether/ethyl acetatesystem, ethyl acetate concentration from 0% to 40%, 12 column volumes)to obtain compound (I-37-b): (120 mg, 0.3023 mmol), the yield was58.53%, white solid. ¹H NMR (400 MHz, MeOD) δ 7.38-7.27 (m, 2H),7.24-7.18 (m, 1H), 7.18-7.09 (m, 1H), 4.38-4.23 (m, 2H), 3.83-3.67 (m,2H), 2.63 (td, J=14.1, 6.0 Hz, 1H), 2.52-2.37 (m, 1H), 2.31 (s, 1H),2.25-2.13 (m, 1H), 2.00-1.84 (m, 3H), 1.82-1.63 (m, 3H), 1.53 (s, 9H).

Step 2:

Compound (I-37-b) (120 mg, 0.30 mmol) was dissolved in tetrahydrofuran(5 mL), then sodium hydride (2 equiv., 0.607 mmol, 60 mass %) was addedthereto, and the reaction was stirred for 2 hours at 50° C. The reactionwas quenched with water, and extracted with ethyl acetate (2×20 mL), thethe organic phase was washed with saline (1×20 mL), dried over Na₂SO₄,filtered and concentrated to obtain compound (I-37-c): (80 mg, 0.22mmol), the yield was 73.4%, white solid. ¹H NMR (400 MHz, MeOD) δ7.31(dt, J=18.7, 8.6 Hz, 3H), 7.15 (d, J=8.5 Hz, 1H), 4.42-4.26 (m, 2H),3.66 (ddd, J=16.1, 12.2, 5.9 Hz, 2H), 2.50 (s, 1H), 2.15 (dd, J=17.3,6.4 Hz, 2H), 1.99-1.79 (m, 4H), 1.77-1.61 (m, 3H), 1.53 (d, J=1.7 Hz,9H). LC-MS: m/z: (M+H)⁺=305.1.

Step 3:

Compound (I-37-c) (80 mg, 0.22 mmol) was dissolved in dichloromethane (2mL), then trifluoroacetic acid (1 mL) was added thereto, and thereaction was stirred for 12 hours at room temperature. The reactionmixture was concentrated, then aq. NaHCO₃ was added thereto, and themixture was extracted with ethyl acetate (2×20 mL), the the organicphase was washed with saline (1×20 mL), dried over Na₂SO₄, filtered andconcentrated to obtain a crude product. The crude product was refined bynormal phase silica gel column (elution conditions: petroleumether/ethyl acetate system, ethyl acetate concentration from 0% to 50%,12 column volumes) to obtain compound (I-37-d): (60 mg, 0.2305 mmol),the yield was 100%, yellow solid. ¹H NMR (400 MHz, MeOD) δ 7.11 (d,J=8.1 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 6.78-6.66 (m, 2H), 4.40-4.29 (m,2H), 3.70-3.57 (m, 4H), 2.10 (d, J=17.5 Hz, 1H), 1.97-1.81 (m, 4H),1.72-1.57 (m, 3H). LC-MS: m/z: (M+H)⁺=261.1.

Step 4:

Compound (I-15-c) (60 mg, 0.1616 mmol) was dissolved in toluene (2 mL),then m-CPBA (1.2 equiv., 0.1939 mmol, 77 mass %) was added thereto atroom temperature, and the reaction was stirred for 2 hours at roomtemperature. Compound (I-37-d) (1.4 equiv., 0.2262 mmol) and DIPEA (2equiv., 0.3231 mmol) were added to the above reaction mixture at roomtemperature sequentially, and the reaction was continued with stirringat room temperature for 12 hours. The reaction was quenched with water,and extracted with ethyl acetate (2×20 mL), the the organic phase waswashed with saline (1×20 mL), dried over Na₂SO₄, filtered andconcentrated to obtain a crude product. The crude product was refined bynormal phase silica gel column (elution conditions:dichloromethane/tetrahydrofuran system, tetrahydrofuran concentrationfrom 0% to 50%, 12 column volumes) to obtain compound (I-37): (15 mg,0.02570 mmol), the yield was 15.91%, yellow solid. ¹H NMR (400 MHz,CDCl₃) δ8.77 (s, 1H), 8.16-8.07 (m, 1H), 8.03 (d, J=7.6 Hz, 1H),7.83-7.75 (m, 1H), 7.56 (dd, J=12.6, 6.1 Hz, 2H), 7.33 (d, J=8.5 Hz,1H), 7.21 (d, J=8.5 Hz, 1H), 5.72 (dd, J=17.0, 10.3 Hz, 1H), 5.13 (dd,J=9.1, 6.1 Hz, 2H), 4.96 (d, J=17.0 Hz, 2H), 4.81 (d, J=7.2 Hz, 2H),4.69 (d, J=6.2 Hz, 2H), 4.41-4.28 (m, 2H), 3.86 (s, 1H), 3.77 (t, J=6.6Hz, 1H), 3.63-3.50 (m, 2H), 2.98 (m, 1H), 2.15 (m, 1H), 1.97 (dd,J=18.9, 9.6 Hz, 2H), 1.78 (d, J=5.0 Hz, 2H), 1.65 (d, J=8.7 Hz, 2H).LC-MS: m/z: (M+H)⁺=584.1.

Embodiment 38

Step 1:

Compound (I-33-a) (150 mg, 0.79260 mmol) was dissolved indichloromethane (2 mL), and then (Boc)₂O (1.2 equiv., 0.95112 mmol) andDIPEA (2 equiv., 1.5852 mmol) were added thereto, and the reaction wasstirred at room temperature for 12 hours. The reaction was quenched withwater and extracted with dichloromethane (2×20 mL), the organic phasewas washed with saline (1×20 mL), dried over Na₂SO₄, filtered andconcentrated to obtain compound (I-38-a): (250 mg, 0.8639 mmol), theyield was 100.0%, yellow solid. ¹H NMR (400 MHz, DMSO) δ 9.25 (s, 1H),7.37 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.6 Hz, 2H), 2.98 (ddd, J=12.0, 8.7,3.3 Hz, 1H), 2.65-2.52 (m, 2H), 2.25 (dd, J=12.5, 2.0 Hz, 2H), 2.11-1.97(m, 2H), 1.83 (ddd, J=25.9, 13.2, 4.0 Hz, 2H), 1.47 (s, 9H).

Step 2:

Potassium tert-butoxide (3 equiv., 1.866 mmol) was dissolved in drytetrahydrofuran (1 mL), and then a solution of tosylmethyl isocyanide(1.5 equiv., 0.933 mmol) in dry tetrahydrofuran (1 mL) was added theretoat room temperature. Compound (I-38-a) (180 mg, 0.6220 mmol) wasdissolved in dry methanol (0.5 mL), the solution was added to the abovereaction mixture, and then the reaction was stirred at room temperaturefor 12 hours. The reaction was quenched with water, and extracted withethyl acetate (2×20 mL), the the organic phase was washed with saline(1×20 mL), dried over Na₂SO₄, filtered and concentrated to obtain acrude product. The crude product was refined by normal phase silica gelcolumn (elution conditions: dichloromethane/methanol system, methanolconcentration from 0% to 10%, 12 column volumes) to obtain compound(I-38-b): (60 mg, 0.1997 mmol), the yield was 32.11%, yellow solid.LC-MS: m/z: (M+H)⁺=244.7.

Step 3:

Compound (I-38-b) (50 mg, 0.16 mmol) was dissolved in dichloromethane (2mL), then trifluoroacetic acid (1 mL) was added thereto, and thereaction was stirred for 12 hours at room temperature. After thereaction mixture was concentrated, aq. NaHCO₃ was added thereto, and themixture was extracted with ethyl acetate (2×20 mL); the organic phasewas washed with saline (1×20 mL), dried over Na₂SO₄, filtered andconcentrated to obtain compound (I-38-c): (50 mg, 0.159 mmol), the yieldwas 96%, yellow solid. LC-MS: m/z: (M+H)⁺=201.1.

Step 4:

Compound (I-15-c) (50 mg, 0.1346 mmol) was dissolved in toluene (2 mL),then m-CPBA (1.2 equiv., 0.1616 mmol, 77 mass %) was added thereto atroom temperature, and the reaction was stirred for 2 hours at roomtemperature. Compound (I-38-c) (50 mg, 0.1346 mmol) and DIPEA (2 equiv.,0.2693 mmol) were added to the above reaction mixture at roomtemperature sequentially, and the reaction was continued with stirringat room temperature for 12 hours. The reaction was quenched with water,and extracted with ethyl acetate (2×20 mL), the the organic phase waswashed with saline (1×20 mL), dried over Na₂SO₄, filtered andconcentrated to obtain a crude product. The crude product was refined bynormal phase silica gel column (elution conditions:dichloromethane/tetrahydrofuran system, tetrahydrofuran concentrationfrom 0% to 30%, 12 column volumes) to obtain compound (I-38): (10 mg,0.01910 mmol), the yield was 14.19%, white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.69 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 8.10 (dd, J=17.9, 7.6 Hz,1H), 7.81-7.72 (m, 1H), 7.63-7.49 (m, 2H), 7.25 (d, J=8.4 Hz, 1H), 7.19(d, J=8.3 Hz, 1H), 5.70 (d, J=6.8 Hz, 1H), 5.15 (d, J=10.1 Hz, 1H),5.14-5.07 (m, 1H), 4.95 (d, J=16.6 Hz, 1H), 4.83 (t, J=6.7 Hz, 2H), 4.71(s, 2H), 2.54 (dd, J=24.9, 12.6 Hz, 2H), 2.30 (d, J=11.2 Hz, 1H), 2.18(d, J=13.5 Hz, 1H), 2.02 (d, J=12.9 Hz, 1H), 1.96-1.80 (m, 2H), 1.78 (d,J=16.1 Hz, 1H), 1.49 (dd, J=26.4, 11.2 Hz, 2H). LC-MS: m/z:(M+H)⁺=524.1.

Embodiment 40

Compound (I-39) (70 mg, 0.12 mmol) was dissolved in a mixture of ethanol(2 mL), tetrahydrofuran (2 mL) and water (2 mL), then lithium hydroxidemonohydrate (15 mg, 0.36 mmol) was added thereto, and the reactionmixture was concentrated after stirring at room temperature for 16hours; the reaction mixture was purified by thin layer chromatography(dichloromethane: ammonia methanol (7 M): ethyl acetate=7:1:1) to obtaina white solid (I-40) (40 mg, 60%). ¹H NMR (400 MHz, Methanol-d₄) δ 8.84(s, 1H), 8.05 (t, J=7.9 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.66 (dd,J=7.6, 0.9 Hz, 1H), 7.63-7.53 (m, 2H), 7.22-7.14 (m, 2H), 5.84-5.74 (m,1H), 5.10-5.07 (m, 2H), 5.06 (q, J=1.3 Hz, 1H), 4.98 (dq, J=17.0, 1.4Hz, 1H), 4.89 (dt, J=6.1, 1.4 Hz, 2H), 2.71 (d, J=6.9 Hz, 1H), 2.59 (s,1H), 2.24 (dd, J=16.4, 7.8 Hz, 2H), 2.04 (d, J=8.5 Hz, 1H), 1.73 (td,J=10.9, 6.8 Hz, 6H). LC-MS: m/z: [M+1]+=543.0.

Embodiment 41

Compound (I-41-1) and compound (I-41-2) can be synthesized by the samemethod as in embodiment 1 using 5-bromo-2-nitropyridine as raw material.Compound 1-41-1: HPLC retention time (RT)=6.17 min (HPLC conditions:mobile phase A was water (containing HCOOH 0.1%), mobile phase B wasacetonitrile; gradient elution: 5% mobile phase B→95% mobile phase B),¹H NMR (400 MHz, Chloroform-d) δ 9.00 (s, 1H), 8.30 (d, J=8.6 Hz, 1H),8.22 (d, J=2.4 Hz, 1H), 7.96 (t, J=7.9 Hz, 1H), 7.73 (dd, J=8.1, 0.8 Hz,1H), 7.55 (dd, J=8.7, 2.4 Hz, 1H), 7.44 (dd, J=7.7, 0.8 Hz, 1H),5.77-5.66 (m, 1H), 5.12-5.05 (m, 1H), 4.97 (dq, J=17.0, 1.4 Hz, 1H),4.76 (dt, J=6.3, 1.3 Hz, 2H), 2.70 (s, 1H), 2.56 (s, 6H), 2.23 (q, J=9.5Hz, 4H), 2.11-2.01 (m, 4H), 1.58 (t, J=10.3 Hz, 6H). LC-MS: m/z:[M+1]⁺=529.1. Compound 1-41-2: HPLC retention time (RT)=6.28 min (HPLCconditions: mobile phase A was water (containing HCOOH 0.1%), mobilephase B was acetonitrile; gradient elution: 5% mobile phase B→95% mobilephase B), ¹H NMR (400 MHz, Chloroform-d) δ8.99 (s, 1H), 8.54 (s, 1H),8.32 (d, J=8.7 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.10 (t, J=7.7 Hz, 1H),7.92 (s, 1H), 7.78 (dd, J=8.1, 0.8 Hz, 1H), 7.47-7.41 (m, 1H), 5.79-5.71(m, 1H), 5.08 (dq, J=10.1, 1.2 Hz, 1H), 4.97 (dq, J=17.0, 1.3 Hz, 1H),4.77 (dt, J=6.2, 1.4 Hz, 2H), 3.99 (s, 1H), 2.75 (d, J=11.0 Hz, 1H),2.52 (s, 6H), 2.32-2.18 (m, 1H), 2.09 (d, J=14.4 Hz, 4H), 1.31 (d,J=22.8 Hz, 4H). LC-MS: m/z: [M+1]⁺=529.1.

With reference to the above embodiments, the compounds shown in Table 1were prepared, and their structural characteristics were as follows:

TABLE 1 List of compounds Compound Structure Characterization dataMethod I-2

¹H NMR (400 MHz, MeOD) δ 8.85 (s, 1H), 8.00 (t, J = 7.9 Hz, 1H), 7.80(d, J = 8.1 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 8.6 Hz, 2H),7.28 (d, J = 8.6 Hz, 2H), 5.78-5.68 (m, 1H), 5.06 (d, J = 10.3 Hz, 1H),4.95 (s, 1H), 4.82 (s, 2H), 3.82-3.76 (m, 1H), 2.81 (s, 1H), 2.71 (s,3H), 2.49 (s, 1H), 2.08 (d, J = 10.9 Hz, 3H), 1.94 (d, J = 15.0 Hz, 3H),1.72 (s, 4H), 1.59 (d, J = 7.0 Hz, 6H). LC-MS: m/z: (M + H)⁺ = 570.3.I-1 I-8

¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 7.93-7.85 (m, 1H), 7.78 (d, J =7.8 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.39 (dd, J = 7.6, 0.7 Hz, 1H),7.19 (d, J = 8.5 Hz, 2H), 5.71 (ddt, J = 16.4, 10.2, 6.2 Hz, 1H), 5.05(dd, J = 10.2, 1.1 Hz, 1H), 4.94 (dd, J = 17.1, 1.3 Hz, 1H), 4.77 (d, J= 6.2 Hz, 2H), 4.11 (d, J = 8.9 Hz, 1H), 3.24 (t, J = 7.0 Hz, 4H),2.52-2.43 (m, 1H), 2.14-2.00 (m, 3H), 1.92 (d, J = 11.2 Hz, 4H), 1.60(s, 6H), 1.45 (dt, J = 14.9, 7.5 Hz, 2H) 1.23-1.08 (m, 2H). LC-MS: m/z:(M + H)⁺ = 540.4. I-1 See embodiment 8 for details I-8-1

¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 7.93-7.85 (m, 1H), 7.78 (d, J =7.8 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.39 (dd, J = 7.6, 0.7 Hz, 1H),7.19 (d, J = 8.5 Hz, 2H), 5.71 (ddt, J = 16.4, 10.2, 6.2 Hz, 1H), 5.05(dd, J = 10.2, 1.1 Hz, 1H), 4.94 (dd, J = 17.1, 1.3 Hz, 1H), 4.77 (d, J= 6.2 Hz, 2H), 4.11 (d, J = 8.9 Hz, 1H), 3.24 (t, J = 7.0 Hz, 4H),2.52-2.43 (m, 1H), 2.14-2.00 (m, 3H), 1.92 (d, J = 11.2 Hz, 4H), 1.60(s, 6H), 1.45 (dt, J = 14.9, 7.5 Hz, 2H) 1.23-1.08 (m, 2H). LC-MS: m/z:(M + H)⁺ = 540.4. After testing, its retention time was unique: HPLCretention time (RT) = 10.78 min (HPLC conditions: mobile phase A waswater (containing HCOOH 0.1%), mobile phase B was acetonitrile; gradientelution: 5% mobile phase B→50% mobile phase B). Therefore, itscyclohexyl moiety was cis or trans. This can be further corroborated bytogether embodiment 8-2. I-1 See embodiment 8-1 for details I-8-2

¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.80(d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 7.6 Hz, 1H),7.29-7.25 (m, 2H), 5.82-5.63 (m, 1H), 5.12-4.91 (m, 2H), 4.78 (d, J =6.2 Hz, 2H), 4.01 (s, 1H), 3.17 (s, 4H), 2.53 (s, 1H), 2.33 (s, 1H),2.06 (d, J = 4.4 Hz, 2H), 1.89 (d, J = 11.6 Hz, 2H), 1.75 (d, J = 14.1Hz, 2H), 1.59 (d, J = 17.2 Hz, 8H), 1.46 (t, J = 13.1 Hz, 2H). LC-MS:540.0 [M + H]⁺. HPLC retention time (RT) = 10.997 min (HPLC conditions:mobile phase A was water (containing HCOOH 0.1%), mobile phase B wasacetonitrile; gradient elution: 5% mobile phase B→50% mobile phase B).See embodiment 8-2 or embodiment 8-3 I-17

¹H NMR (400 MHz, CDCl₃) δ 8.84 (d, J = 3.7 Hz, 1H), 7.94 (dd, J = 14.8,6.9 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.58-7.50 (m, 2H), 7.42 (dd, J =7.5, 4.1 Hz, 1H), 7.22 (dd, J = 15.8, 8.5 Hz, 2H), 5.71 (dd, J = 11.5,5.4 Hz, 2H), 5.07 (d, J = 10.2 Hz, 1H), 4.95 (d, J = 17.1 Hz, 1H), 4.77(d, J = 6.1 Hz, 2H), 2.82-2.72 (m, 1H), 2.60 (s, 1H), 2.12-2.01 (m, 3H),1.92 (d, J = 12.5 Hz, 1H), 1.81-1.67 (m, 3H), 1.62 (s, 6H), 1.54-1.43(m, 1H), 0.93-0.78 (m, 3H), 0.52 (s, 2H). LC-MS: m/z: (M + H)⁺ = 568.4.I-7 I-39

¹H NMR (400 MHz, Methanol-d₄) δ 8.85 (d, J = 1.1 Hz, 1H), 8.05 (td, J =7.9, 4.8 Hz, 1H), 7.96-7.86 (m, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.59(ddd, J = 9.2, 4.6, 2.3 Hz, 2H), 7.25-7.19 (m, 1H), 7.19-7.11 (m, 1H),5.78 (ddt, J = 16.5, 10.1, 6.1 Hz, 1H), 5.12-5.07 (m, 2H), 5.06 (t, J =1.3 Hz, 1H), 4.98 (dd, J = 17.0, 1.4 Hz, 1H), 4.90 (d, J = 1.4 Hz, 2H),4.25-4.19 (m, 1H), 4.14 (dd, J = 14.1, 7.1 Hz, 1H), 2.34-2.12 (m, 2H),2.07 (dd, J = 17.0, 4.1 Hz, 1H), 1.99-1.82 (m, 1H), 1.74-1.65 (m, 2H),1.65-1.53 (m, 2H) 1.31 (d, J = 4.2 Hz, 3H) 1.29-1.25 (m, 2H). LC-MS:m/z: [M + H]⁺ = 571.1. I-4

Effect Embodiment 1

I. Inhibitory Effect of Compound on WEE1 Kinase In Vitro

Test Method:

The tested compounds were screened on WEE1 kinase with ATP concentrationof K_(m) by ELISA. Compounds were screened on WEE1 kinase to evaluatethe kinase inhibitory activity of the tested compounds. In the detectionprocess, the initial concentration of the tested compounds was allselected as 100 nM, and each compound was selected with 6 gradientdilution concentrations, the gradient dilution ratio was 4-fold, and tworeplicate wells were detected for each concentration, MK1775 was used asthe standard control.

WEE1, purchased from CarnaBiosciences, Inc., Item No. 05-177; dimethylsulfoxide, purchased from Sigma-Aldrich, Item No. D8418; ATP, purchasedfrom Sigma-Aldrich, Item No. A7699; DTT solution, purchased fromSigma-Aldrich, Item No. 43816; protein tyrosine kinase (PTK) substrate(poly-Glu-Tyr), purchased from Sigma-Aldrich, Item No. P4476; P-Tyr(PY99), purchased from Santa Cruz, Item No. sc-7020; Anti-mouse IgGHRP-linked Antibody, purchased from Santa Cruz, Item No. 7076S; TMBliquid Substrate System, purchased from Sigma-Aldrich, Item No. T0440;Costar Stripwell Microplate No Lid 1×8 Flat Bottom, Certified HighBinding, purchased from Sigma-Aldrich, Item No. 42592; 96-well compoundplate, purchased from Thermo Scientific, Item No. 267245.

Test Steps:

1. Coating substrate: 1) An appropriate volume of substrate storagesolution protein tyrosine kinase (PTK) substrate (poly-Glu-Tyr) wastaken, diluted 10 times with PBS, and the concentration was diluted from250 mg/mL to 25 mg/mL. The mixture was added to a high adsorption96-well plate at 125 μL per well. The plate was placed in an incubatorat 37° C. for overnight coating. 2) After 24 hours, the 96-well platewas taken out, the liquid in the 96-well plate was poured out, cleanedwith washing buffer for 3 times, and the incubator at 37° C. wasinverted and dried for 2 hours.

2. Compound preparation and transfer: 1) compound dilution: 10 mM of thetest compound storage solution was taken, the compound in 96-wellcompound plate was diluted with DMSO in multiple steps to obtain theinitial concentration of 100× compound as the first concentration, andthen DMSO was used for 4-fold gradient dilution, for a total of 6concentrations; after that, 2 μL of the gradient dilution solution wasadded to 48 μL of 1× reaction buffer respectively to prepare 4×compound; 2) 4× compounds were transferred: 10 μL of 4× compounds fromthe 96-well compound plate configured in the previous step weretransferred into the dried high adsorption 96-well plate; 10 μL of thefollowing liquids were added to the compound-free control wells andATP-control wells: 2 μL of DMSO was added to 48 μL of 1× reactionbuffer.

3. Enzyme reaction stage: 1) WEE1 kinase and ATP were prepared into 2×enzyme solution and 4×ATP solution respectively with 1× reaction buffer.In this screening, the final concentration of WEE1 kinase was: 0.15ng/μL and the final concentration of ATP was: 12 M; 2) 20 μL of enzymesolution of 2 was added to the high adsorption 96-well plate; 3) 10 μLof 4×ATP solution was added to the high adsorption 96-well plate and 10μL of 1× reaction buffer was added to the ATP-control group; 4) theplate was placed in HERAEUS Multifuge X1R centrifuge at 2000 rpm for 20s and then placed at room temperature and reacted for 60 min.

4. Reaction termination stage: 1) the reaction mixture in the plate waspoured out, 200 μL of washing buffer was added to each well, and washedfor 5 times; the primary antibody P-Tyr (PY99) (dilution ratio 1:2000)was added, 100 μL per well, at room temperature for 30 min. 2) Theprimary antibody in the plate was poured out, 200 μL of washing bufferwas added to each well, and washed for 5 times; the second antibodyAnti-mouse IgG HRP-linked Antibody (dilution ratio 1:2000) was added,100 μL per well, at room temperature for 30 min. 3) The secondaryantibody in the plate was poured out, washed 5 times with washingbuffer, and TMB was added, 100 μL per well, and colored for 10-30 min,depending on the color depth. The reaction was terminated with 1Nsulfuric acid before reading.

5. Detection and data processing: 1) The light absorption at 450 nM wasread on ThermoScientific MultiScan GO, and the background was read at650 nM at the same time. 2) Graphpad Prism 5.0 was used to fitLog(inhibitor) vs. response-Variable slope (four parameters) curves tothe data, and the corresponding IC₅₀ (half maximal inhibitoryconcentration) was calculated.

II. The Data of the Test Result.

The structure of the control samples used in the tests was shown inTable 2.

TABLE 2 Structure of control sample Control sample number Chemicalstructure Control 1 (AZD1775/MK1775)

Control 2 (WO 2019/096322 Al Patent Compound)

The test results were detailed in Table 3.

TABLE 3 Test results of WEEE 1 enzyme inhibitory activity and cellinhibitory activity Compound WEE1 Compound WEE1 number IC₅₀, nM numberIC₅₀, nM Control 1 2.57 Control 2 1.98 I-1-1 1.90 I-1-2 2.08 I-2 2.57I-3-1 0.35 I-3-2 0.66 I-5 7.15 I-6 6.76 I-7 6.53 I-8 1.52 I-8-1 1.52I-8-2 3.52 I-15-1 1.52 I-15-2 1.68 I-17 4.05 I-19 3.89 I-20 3.45 I-230.71 I-31 2.05 I-32 7.39 I-33 4.22 I-34 3.30 I-36-2 2.92 I-37 1.99 I-381.68 I-39 2.08 I-40 4.58 I-41-1 2.11 I-41-2 2.74

Conclusion: As shown in Table 3, the compounds of the present disclosurehave a good inhibitory effect on Wee1 kinase.

Effect Embodiment 2 Bioavailability Test In Vivo in Mice

I. Experimental Animals and Test Products

1. Experimental Animal

Species Strain Certificate number Weight (g) Number (pcs) Mice ICR20180006002806 20 60

All the above were provided by Shanghai Sino-British SIPPR Lab. AnimalLtd.

2. Preparation of Test Products

2.1 Preparation of Mother Liquor

404.6 μL of DMSO was added to the compound powder of the presentdisclosure until the compound was completely dissolved, and 50 mg/mLmother liquor was prepared in a clarified state.

2.2 Preparation of Administration Solution

The compound of the present disclosure: 24 μL of mother liquor wasaccurately measured, diluted to 4 mL according to the ratio of 0.9%normal saline: PEG400=8:2, the preparation concentration was 0.3 mg/mL,the solution was in a clarified state, and it was used as intravenousadministration solution. In addition, 80 μL mother liquor was accuratelymeasured, and 0.5% CMC-Na was added to 8 mL to grind it into a uniformsuspension with a concentration of 0.5 mg/mL, which was used asintragastric administration solution.

II. Animal Experiments

Intravenous group: 24 ICR mice, 20±2 g, were given the intravenousadministration solution of the compound of the present disclosure byintravenous injection, with the volume of 10 mL/kg, with the dose of 3mg/kg, the blood was taken from the fundus venous plexus of mice, 2, 5,15, 30, 60, 90, 120, 240, 360, 480, 600 and 1440 minutes before andafter administration.

Intragastric group: 24 ICR mice, 20±2 g, were given the intragastricadministration solution of the compound of the present disclosure byintragastric injection, with the volume of 20 mL/kg, with the dose of 10mg/kg, the blood was taken from the fundus venous plexus of mice, 5, 15,30, 60, 90, 120, 240, 360, 480, 600 and 1440 minutes before and afteradministration.

Blood sample was centrifuged at 8000 rpm for 5 min, and the plasma wasstored in a centrifuge tube at −20° C. for later use.

III. Treatment of Plasma Samples

1. Preparation of Standard Curve

The concentration range of standard working solution was 60, 20, 6, 2,0.6, 0.2, 0.1, 0.04 μg/mL.

47.5 μL of blank mouse plasma was taken and 2.5 μL of standard curveworking solution was added to prepare samples with a series ofconcentrations of 3, 1, 0.3, 0.1, 0.03, 0.01, 0.005, 0.002 and 0.001g/mL; the samples were vortexed evenly, and 300 μL of acetonitrilecontaining internal standard (Propranolol, 25 ng/mL) was added toprecipitate protein, the samples were vortexed for 10 min, 6000 g, 4°C., centrifuged for 10 min, and the supernatant was injected into a96-well plate.

2. Treatment of QC Sample

The concentration range of QC working solution: Low: 0.06 μg/mL; Middle:1.6 μg/mL; High: 48 μg/mL.

47.5 μL of blank mouse plasma was taken and 2.5 μL of QC workingsolution was added to prepare samples with a series of concentrations of2.4, 0.08, 0.003 μg/mL; the samples were vortexed evenly, and 300 μL ofacetonitrile containing internal standard (Propranolol, 25 ng/mL) wasadded to precipitate protein, the samples were vortexed for 10 min, 6000g, 4° C., centrifuged for 10 min, and the supernatant was injected intoa 96-well plate.

3. Treatment of Plasma Samples

300 μL of acetonitrile containing internal standard (Propranolol, 25ng/mL) was added to 50 μL of plasma samples to precipitate protein,vortexed for 10 min, 6000 g, 4° C., centrifuged for 10 min; thesupernatant before intravenous injection for 1 hour was taken, diluted10 times with acetonitrile containing internal standard, the restsupernatant was kept undiluted, centrifuged for 10 min again at 6000 g,4° C., and the supernatant was taken and then injected into a 96-wellplate.

IV. Experimental Results of Bioavailability in Mice

1. Test Parameters

Dose; peak concentration: C_(max); peak time: T_(max); area under thedrug-time curve from AUC_(last) 0 to time t; half-life: T_(1/2); meanretention time: MRT; clearance: Cl; apparent distribution volume: V_(z);steady-state distributed volume: V_(ss); absolute bioavailability: F.

2. Pharmacokinetics Data of Mice

The pharmacokinetic parameters of the compound in mice after intravenousinjection or intragastric administration were shown in Table 4 and Table5 below.

TABLE 4 Pharmacokinetic parameters of compounds in mice Control 1(MK1775) Control 2 I-1-1 I-8 iv po iv po iv po iv po Dose mg/kg 3 10   3    10    3 10    3 10    C_(max) ng/mL 773.8 ± 53.79 205.2 ± 124.5646.4 ± 76.85 27.79 ± 4.76 700.8 ± 142.5 245.2 ± 220.3 644.0 ± 132.258.08 ± 1.09  T_(max) h 0.05 ± 0.03 0.33 ± 0.14 0.03  1.67 ± 2.02 0.032.50 ± 1.32 0.03 AUC_(last) (h) * (ng/mL) 273.1 ± 21.34 151.7 ± 62.14261.52 ± 26.93 80.15 ± 9.62 372.5 ± 24.38 528.6 ± 331.1 317.5 ± 34.41637.9 ± 302.3 T_(1/2) h 0.65 ± 0.03 3.10 ± 0.22  1.37 ± 0.33  2.51 ±1.85 4.31 ± 1.51 3.10 ± 9.02 1.22 ± 0.10 1.57 ± 0.39 MRT h 0.42 ± 0.024.33 ± 0.28  0.86 ± 0.16  3.78 ± 1.56 1.75 ± 0.46 4.33 ± 9.02 1.11 ±0.08 3.47 ± 1.22 Cl L/kg * h 10.99 ± 0.87  /  11.3 ± 1.20 / 7.74 ± 0.36/ 9.29 ± 0.85 / Vz L/kg 10.31 ± 1.12  /  22.2 ± 3.29 / 48.52 ± 18.38 /16.33 ± 2.48  / Vss L/kg 4.58 ± 0.44 /  9.69 ± 0.96 / 13.61 ± 3.95  /10.32 ± 0.86  / F % 16.67  9.19 42.57 60.27

TABLE 5 Pharmacokinetic parameters of compounds in mice I-8-1 iv po Dosemg/kg 3 10 C_(max) ng/mL 644.0 ± 132.2 58.08 ± 7.09  T_(max) h 0.03 1.67± 0.29 AUC_(last) (h)*(ng/mL) 317.5 ± 34.41 637.9 ± 302.3 T_(1/2) h 1.22± 0.10 1.57 ± 0.39 MRT h 1.11 ± 0.08 3.47 ± 1.22 Cl L/kg*h 9.29 ± 0.85 /Vz L/kg 16.33 ± 2.48  / Vss L/kg 10.32 ± 0.86  / F % 60.27

Conclusion: The compound of the present disclosure can significantlyimprove the pharmacokinetics of mice.

Effect Embodiment 3 Bioavailability Test In Vivo in Cynomolgus Monkey

I. Experimental Animals and Subjects

Twelve male Non-Naïve cynomolgus monkeys were purchased fromGuangxiGuidong Primate Development Experiment Co. LTD.

Administration Administration Number Dose concentration volumeAdministration Sample Grouping Subjects Male (mg/kg) (mg/mL) (mL/kg)mode collection 1 I-8-1 3 3 1.5 2 IV Plasma 2 3 20 4 5 PO* Plasma 3AZD1775 3 3 1.5 2 IV Plasma 4 3 20 4 5 PO* Plasma Note: *indicates theoral fasting, the food was withdrawn from 16:00-17:00 p.m. the daybefore the administration, and the food was added about 4 hours afterthe administration in the morning of the administration.

II. Preparation of Subjects

The test product was prepared with free alkali concentration, and thepurity was not converted.

III. Preparation of Administration Solution

I. Preparation of I-8-1:

54.31 mg of I-8-1 was accurately weighed, and 1.08 mL of DMSO was added,then the mixture was vortexed for 1 min, sonicated for 15 min, and thendiluted to 36 mL according to the ratio of 10% HP-β-cyclodextrin(prepared by normal saline): PEG=8:2, vortexed for 1 min. A colorlessclarified administration solution (the pH value was about 7) at aconcentration of 1.5 mg/mL was prepared for intravenous administrationto Group 1.

300.9 mg of I-8-1 was accurately weighed, and 75 mL of 0.5% CMC-Na wasadded, the mixture was fully ground and stirred for 5 min. A whitesuspension (the pH value was about 7) at a concentration of 4 mg/mL wasprepared for oral administration to Group 2.

2. Preparation of AZD1775:

54.05 mg of AZD1775 was accurately weighed, and 1.08 mL of DMSO wasadded, then he mixture was vortexed for 1 min, sonicated for 15 min, andthen diluted to 36 mL according to the ratio of 10%-D-cyclodextrin(prepared by normal saline): PEG=8:2, vortexed for 1 min. A yellowclarified administration solution (the pH value was about 7) at aconcentration of 1.5 mg/mL was prepared for intravenous administrationto Group 3.

300.7 mg of AZD1775 was accurately weighed, and 75 mL of 0.5% CMC-Na wasadded, the mixture was fully ground and stirred for 5 min. A yellowsuspension (the pH value was about 7) at a concentration of 4 mg/mL wasprepared for oral administration to Group 4.

IV. Animal Experiments

1. Dose and Mode of Administration

Before administration, all animals were fasted overnight (approximately12 hours) and fed as required and administered according to the tablebelow.

Subjects Subjects Solution Administration Weight Dose concentration*volume Dose Route of Grouping Gender Subjects (kg) (mg/kg) (mg/ml)(mL/kg) (mL) administration 1 M I-8-1 2.30 3 1.5 2 4.6 IV 1 M I-8-1 2.303 1.5 2 4.6 IV 1 M I-8-1 2.45 3 1.5 2 5.0 IV 2 M I-8-1 2.50 20 4 5 13 PO2 M I-8-1 2.85 20 4 5 14 PO 2 M I-8-1 2.45 20 4 5 12 PO 3 M AZD1775 2.353 1.5 2 4.8 IV 3 M AZD1775 2.55 3 1.5 2 5.2 IV 3 M AZD1775 2.35 3 1.5 24.8 IV 4 M AZD1775 2.20 20 4 5 11 PO 4 M AZD1775 2.30 20 4 5 12 PO 4 MAZD1775 2.50 20 4 5 13 PO *Drug concentration was calculated accordingto free base. **All animals were fasted overnight before administration(withdrawn at 16:00-17:00 pm approximately the day beforeadministration) and fed 4 hours after administration on the morning ofthe day of administration.

2. Collection and Treatment of Plasma Samples

Intravenous group: before administration (0 h), 0.033 h, 0.083 h, 0.25h, 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h afteradministration.

Oral group: before administration (0 h), 0.083 h, 0.25 h, 0.5 h, 1.5 h,1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h after administration.

Blood samples were collected by puncture through lower limb vein orother suitable blood vessels at 1 mL/time point (3 mL of blood sampleswere collected from each animal before administration), anticoagulatedwith heparin sodium, and placed on ice after collection. Plasma wasseparated at 2200 g/min, 10 min, 2-8° C., plasma samples were stored ina −80° C. refrigerator before being transferred to the client. Plasmasamples are stored in dry ice and transferred to the client. The finaltreatment of the sample will be recorded in the experimental record.

V. Treatment of Plasma Samples

I. Preparation of Standard Curve

The concentration range of standard working solution was 60, 20, 6, 2,0.6, 0.2, 0.1, 0.04, 0.02 μg/mL.

47.5 μL of blank cynomolgus monkey plasma was taken and 2.5 μL ofstandard curve working solution was added to prepare samples with aseries of concentrations of 3, 1, 0.3, 0.1, 0.03, 0.01, 0.005, 0.002 and0.001 g/mL; the samples were vortexed evenly, and 300 μL of acetonitrilecontaining internal standard (Propranolol, 25 ng/mL) was added toprecipitate protein, the samples were vortexed at 6000 g, centrifugedfor 10 min. 80 μL of supernatant was injected into a 96-well plate.

2. Treatment of QC Sample

The concentration range of QC working fluid: Low: 0.06 μg/mL; Middle:1.6 μg/mL; High: 48 g/mL.

47.5 μL of blank cynomolgus monkey plasma was taken and 2.5 μL ofstandard curve working solution was added to prepare samples with aseries of concentrations of 2.4, 0.08 and 0.003 μg/mL; the samples werevortexed evenly, and 300 μL of acetonitrile containing internal standard(Propranolol, 25 ng/mL) was added, the samples were vortexed at 6000 g,centrifuged for 10 min. 80 μL of supernatant was injected into a 96-wellplate.

3. Treatment of Plasma Samples

300 μL of acetonitrile was added to 50 μL of plasma samples containinginternal standard (Propranolol, 25 ng/mL) to precipitate protein,vortexed for 10 min, centrifuged at 6000 g for 10 min, afterI-8-1&AZD1775 intravenous injection group was diluted 10 times withinternal standard acetonitrile (Propranolol, 25 ng/mL) at the time pointbefore 1 hour, the remaining supernatant was not diluted, centrifugedagain at 6000 g at 4° C. for 10 min, and the supernatant was taken andinjected into a 96 well plate.

VI. Experimental Results of Bioavailability in Cynomolgus Monkeys

1. Test Parameters

Dose; peak concentration: C_(max); peak time: T_(max); area under thedrug-time curve from AUC_(last) 0 to time t; half-life: T_(1/2); meanretention time: MRT; clearance: Cl; apparent distribution volume: V_(z);steady-state distributed volume: V_(ss); absolute bioavailability: F.

2. Pharmacokinetics Data

The pharmacokinetic parameters of the compound in cynomolgus monkeysafter intravenous injection or intragastric administration were shown inTable 6 below.

TABLE 6 Pharmacokinetic parameters of compounds in cynomolgus monkeysParameters AZD1775-iv AZD1775-po I-8-1-iv I-8-1-po Dose mg/kg 3 20 3 20C_(max) ng/mL  1202 ± 134.2 1627. ± 243.7 838.4 ± 190.0 720.8 ± 260.4T_(max) h 2.69 ± 4.60 2.00 0.03 4.50 ± 2.60 AUC_(last) (h)*(ng/mL) 4494± 1719  8155 ± 818.2 957.6 ± 126.3 6548 ± 3043 AUC_(extra) (h)*(ng/mL)47.62 ± 58.18 8.46 ± 1.91 16.11 ± 9.34  187.03 ± 166.00 AUCtot(h)*(ng/mL) 4542 ± 1777  8163 ± 819.7 973.8 ± 131.4 6735 ± 3201 thalf h2.78 ± 0.26 2.03 ± 1.22 2.05 ± 1.24 3.71 ± 0.72 MRT h 6.53 ± 2.51 3.58 ±0.07 3.17 ± 0.82 7.91 ± 2.00 Clearance L/h/kg 0.72 ± 0.23 / 3.12 ± 0.43/ Vz L/kg 2.84 ± 0.76 / 8.78 ± 4.22 / Vss L/kg 4.33 ± 0.74 / 9.67 ± 1.32/ BA % 27.22 102.56

Conclusion: The compound of the present disclosure can significantlyimprove the pharmacokinetics of cynomolgus monkeys.

Although the specific embodiments of the present disclosure have beendescribed above, those skilled in the art should understand that theseare only examples, various changes or modifications can be made to theseembodiments without departing from the principle and essence of thepresent invention. Therefore, the protection scope of the presentdisclosure is defined by the appended claims.

1. A pyrazolone-fused pyrimidine compound represented by formula II, apharmaceutically acceptable salt thereof, a solvate thereof, a solvateof the pharmaceutically acceptable salt thereof, a metabolite thereof ora prodrug thereof:

wherein, A is C₃-C₂₀ cycloalkyl substituted by one or two R¹; X is CH orN; R¹ is independently halogen, —OR¹⁻¹, —SR¹⁻², —CN, —NR¹⁻³R¹⁻⁴,—C(═O)R¹⁻⁵, —C(═NR¹⁻⁶)R¹⁻⁷, ═N—O—R¹⁻⁹ or “C₂-C₇ alkenyl, C₂-C₈ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇heteroaryl” optionally substituted by one, two or three R¹⁻⁸; R¹⁻¹ isindependently “C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇ heteroaryl”optionally substituted by one, two or three R¹⁻¹⁻¹; R¹⁻¹⁻¹ isindependently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇ alkyl,C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or“amino substituted by one or two R¹⁻¹⁻¹⁻¹”; R¹⁻¹⁻¹⁻¹ is independentlyC₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻² is independently hydrogen or“C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻²⁻¹; R¹⁻²⁻¹ is independentlyhydrogen, halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇ alkyl, C₁-C₇alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or“amino substituted by one or two R¹⁻²⁻¹⁻¹”; R¹⁻²⁻¹⁻¹ is independentlyC₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³ and R¹⁻⁴ are independentlyhydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻², —C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶,—S(═O)₂NR¹⁻³⁻⁷R¹⁻³⁻⁸, —C(═O)NR¹⁻³⁻⁹R¹⁻³⁻¹⁰ or “C₁-C₇ alkyl, C₂-C₇alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl,C₆-C₁₀ aryl or C₁-C₇ heteroaryl” optionally substituted by one, two orthree R¹⁻³⁻¹¹; or, R¹⁻³ and R¹⁻⁴ together with the nitrogen atom theyare attached to form a C₃-C₁₄ heterocycloalkyl optionally substituted byone, two or three R¹⁻³⁻¹²; one or more methylenes in the C₃-C₁₄heterocycloalkyl are optionally and independently substituted by oxygenatom, sulfur atom, sulfinyl, sulfonyl, carbonyl, vinylidene or—N(R¹⁻³⁻¹³)—; R¹⁻³⁻¹³ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;R¹⁻³⁻¹ and R¹⁻³⁻² are independently “C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl or C₆-C₁₀ aryl”optionally substituted by one or two R¹⁻³⁻¹⁻¹; R¹⁻³⁻¹⁻¹ is independentlyC₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻³ is independently hydrogen, —CN,C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻⁵,R¹⁻³⁻⁶, R¹⁻³⁻⁷, R¹⁻³⁻⁸, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰ are independently hydrogen,C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl or C₃-C₁₄ cycloalkyl; or,R¹⁻³⁻⁵ and R¹⁻³⁻⁶ together with the nitrogen atom they are attached toform a C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R¹⁻³⁻⁵⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkylare optionally and independently substituted by oxygen atom, sulfuratom, sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻⁵⁻²)—;R¹⁻³⁻⁵⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻⁵⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; or, R¹⁻³⁻⁷ and R¹⁻³⁻⁸together with the nitrogen atom they are attached to form a C₃-C₁₄heterocycloalkyl optionally substituted by one, two or three R¹⁻³⁻⁷⁻¹;one or more methylenes in the C₃-C₁₄ heterocycloalkyl are optionally andindependently substituted by oxygen atom, sulfur atom, sulfinyl,sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻⁷⁻²)—; R¹⁻³⁻⁷⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻⁷⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; or, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰together with the nitrogen atom they are attached to form a C₃-C₁₄heterocycloalkyl optionally substituted by one, two or three R¹⁻³⁻⁹⁻¹;one or more methylenes in the C₃-C₁₄ heterocycloalkyl are optionally andindependently substituted by oxygen atom, sulfur atom, sulfinyl,sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻⁹⁻²)—; R¹⁻³⁻⁹⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻⁹⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻¹¹ is independentlyhalogen, hydroxyl, amino, mercapto, cyano, C₁-C₇ alkyl, C₁-C₇ alkoxy,C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻³⁻¹¹”; R¹⁻³⁻¹¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻³⁻¹² is independently halogen, hydroxyl, amino, mercapto,cyano, C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻³⁻¹²⁻¹”; R¹⁻³⁻¹²⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵ is independentlyhydrogen, —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or “C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, orC₁-C₇ heteroaryl” optionally substituted by one, two or three R¹⁻⁵⁻⁴;R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl, C₂-C₇alkenyl, C₂-C₇ alkynyl or C₃-C₁₄ cycloalkyl; or, R¹⁻⁵⁻¹ and R¹⁻⁵⁻²together with the nitrogen atom they are attached to form a C₃-C₁₄heterocycloalkyl optionally substituted by one, two or three R¹⁻⁵⁻¹⁻¹;one or more methylenes in the C₃-C₁₄ heterocycloalkyl are optionally andindependently substituted by oxygen atom, sulfur atom, sulfinyl,sulfonyl, carbonyl, vinylidene or —N(R¹⁻⁵⁻¹⁻²)—; R¹⁻⁵⁻¹⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻¹⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ is independentlyhydrogen, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl; R¹⁻⁵⁻⁴ isindependently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇ alkyl,C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or“amino substituted by one or two R¹⁻⁵⁻⁴⁻¹”; R¹⁻⁵⁻⁴⁻¹ is independentlyC₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁶ is independently hydrogen, —CN,—OH or “C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻⁶⁻¹; R¹⁻⁶⁻¹ is independentlyhalogen, hydroxyl, amino, mercapto, cyano, C₁-C₇ alkyl, C₁-C₇ alkoxy,C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁶⁻¹⁻¹”; R¹⁻⁶⁻¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻⁷ is independently hydrogen, —OR¹⁻⁷⁻¹, —NR¹⁻⁷⁻²R¹⁻⁷⁻³ or“C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻⁷⁻⁴; R¹⁻⁷⁻¹ is independentlyhydrogen, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl; R¹⁻⁷⁻² andR¹⁻⁷⁻³ are independently C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl orC₃-C₁₄ cycloalkyl; or, R¹⁻⁷⁻² and R¹⁻⁷⁻³ together with the nitrogen atomthey are attached to form a C₃-C₁₄ heterocycloalkyl optionallysubstituted by one, two or three R¹⁻⁷⁻²⁻¹; one or more methylenes in theC₃-C₁₄ heterocycloalkyl are optionally and independently substituted byoxygen atom, sulfur atom, sulfinyl, sulfonyl, carbonyl, vinylidene or—N(R¹⁻⁷⁻²⁻²)—; R¹⁻⁷⁻²⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻⁷⁻²⁻² is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;R¹⁻⁷⁻⁴ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻⁷⁻⁴⁻¹”; R¹⁻⁷⁻⁴⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁸ is independentlyoxo, halogen, —OH, amino, mercapto, cyano, C₁-C₇ alkyl, C₁-C₇ alkoxy,C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁸⁻¹”; R¹⁻⁸⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻⁹ is independently hydrogen or C₁-C₇ alkyl; R² is —OR²⁻¹,cyano, carboxyl; or “C₂-C₇ alkyl, C₃-C₁₄ cycloalkyl or C₃-C₁₄heterocycloalkyl” optionally substituted by one, two or three R²⁻²; R²⁻¹is C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl; R²⁻² is independentlyhalogen, hydroxyl, amino, C₁-C₇ alkyl, C₁-C₇ alkoxy, C₃-C₁₄ cycloalkylor C₃-C₁₄ heterocycloalkyl; in any one of the above cases, theheteroatoms in the C₃-C₁₄ heterocycloalkyl, C₁-C₇ heteroaryl areindependently selected from one or more of boron, silicon, oxygen,sulfur, selenium, nitrogen and phosphorus; the number of heteroatoms isindependently 1, 2, 3 or
 4. 2. The pyrazolone-fused pyrimidine compoundrepresented by formula II according to claim 1, the pharmaceuticallyacceptable salt thereof, the solvate thereof, the solvate of thepharmaceutically acceptable salt thereof, the metabolite thereof or theprodrug thereof, wherein, the compound is a pyrazolone-fused pyrimidinecompound represented by formula I:

wherein, A is C₃-C₂₀ cycloalkyl substituted by one or two R¹; R¹ isindependently halogen, —OR¹⁻¹, —SR¹⁻², —CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵,—C(═NR¹⁻⁶)R¹⁻⁷ or “C₂-C₇ alkenyl, C₂-C₈ alkynyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻⁸; R¹⁻¹ is independently “C₁-C₇alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻¹⁻¹; R¹⁻¹⁻¹ is independentlyhalogen, hydroxyl, amino, mercapto, cyano, C₁-C₇ alkyl, C₁-C₇ alkoxy,C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻¹⁻¹⁻¹”; R¹⁻¹⁻¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻² is independently hydrogen, or “C₁-C₇ alkyl, C₂-C₇alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl,C₆-C₁₀ aryl, or C₁-C₇ heteroaryl” optionally substituted by one, two orthree R¹⁻²⁻¹; R¹⁻²⁻¹ is independently hydrogen, halogen, hydroxyl,amino, mercapto, cyano, C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio,C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻²⁻¹⁻¹”; R¹⁻²⁻¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹,—C(═O)R¹⁻³⁻², —C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶, —S(═O)₂NR¹⁻³⁻⁷R¹⁻³⁻⁸,—C(═O)NR¹⁻³⁻⁹R¹⁻³⁻¹⁰ or “C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇heteroaryl” optionally substituted by one, two or three R¹⁻³⁻¹¹; or,R¹⁻³ and R¹⁻⁴ together with the nitrogen atom they are attached to forma C₃-C₁₄ heterocycloalkyl optionally substituted by one, two or threeR¹⁻³⁻¹²; one or more methylenes in the C₃-C₁₄ heterocycloalkyl areoptionally and independently substituted by oxygen atom, sulfur atom,sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻¹³)—; R¹⁻³⁻¹³ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻¹ and R¹⁻³⁻² areindependently “C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl or C₆-C₁₀ aryl” optionallysubstituted by one or two R¹⁻³⁻¹⁻¹; R¹⁻³⁻¹⁻¹ is independently C₁-C₇alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻³ is independently hydrogen, —CN, C₁-C₇alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻¹,R¹⁻³⁻⁶, R¹⁻³⁻⁷, R¹⁻³⁻⁸, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰ are independently C₁-C₇alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl or C₃-C₁₄ cycloalkyl; or, R¹⁻³⁻⁵ andR¹⁻³⁻⁶ together with the nitrogen atom they are attached to form aC₃-C₁₄ heterocycloalkyl optionally substituted by one, two or threeR¹⁻³⁻⁵⁻¹; one or more methylenes in the C₃-C₁₄ heterocycloalkyl areoptionally and independently substituted by oxygen atom, sulfur atom,sulfinyl, sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻⁵⁻²)—; R¹⁻³⁻⁵⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻⁵⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; or, R¹⁻³⁻⁷ and R¹⁻³⁻⁸together with the nitrogen atom they are attached to form a C₃-C₁₄heterocycloalkyl optionally substituted by one, two or three R¹⁻³⁻⁷⁻¹;one or more methylenes in the C₃-C₁₄ heterocycloalkyl are optionally andindependently substituted by oxygen atom, sulfur atom, sulfinyl,sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻⁷⁻²)—; R¹⁻³⁻⁷⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻⁷⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; or, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰together with the nitrogen atom they are attached to form a C₃-C₁₄heterocycloalkyl optionally substituted by one, two or three R¹⁻³⁻⁹⁻¹;one or more methylenes in the C₃-C₁₄ heterocycloalkyl are optionally andindependently substituted by oxygen atom, sulfur atom, sulfinyl,sulfonyl, carbonyl, vinylidene or —N(R¹⁻³⁻⁹⁻²)—; R¹⁻³⁻⁹⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻⁹⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻¹¹ is independentlyhalogen, hydroxyl, amino, mercapto, cyano, C₁-C₇ alkyl, C₁-C₇ alkoxy,C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻³⁻¹¹”; R¹⁻³⁻¹¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻³⁻¹² is independently halogen, hydroxyl, amino, mercapto,cyano, C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻³⁻¹²⁻¹”; R¹⁻³⁻¹²⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵ is independentlyhydrogen, —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or “C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, orC₁-C₇ heteroaryl” optionally substituted by one, two or three R¹⁻⁵⁻⁴;R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl, C₂-C₇alkenyl, C₂-C₇ alkynyl or C₃-C₁₄ cycloalkyl; or, R¹⁻⁵⁻¹ and R¹⁻⁵⁻²together with the nitrogen atom they are attached to form a C₃-C₁₄heterocycloalkyl optionally substituted by one, two or three R¹⁻⁵⁻¹⁻¹;one or more methylenes in the C₃-C₁₄ heterocycloalkyl are optionally andindependently substituted by oxygen atom, sulfur atom, sulfinyl,sulfonyl, carbonyl, vinylidene or —N(R¹⁻⁵⁻¹⁻²)—; R¹⁻⁵⁻¹⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻¹⁻² isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ is independentlyhydrogen, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl; R¹⁻⁵⁻⁴ isindependently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇ alkyl,C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or“amino substituted by one or two R¹⁻⁵⁻⁴⁻¹”; R¹⁻⁵⁻⁴⁻¹ is independentlyC₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁶ is independently hydrogen, —CN,—OH or “C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻⁶⁻¹; R¹⁻⁶⁻¹ is independentlyhalogen, hydroxyl, amino, mercapto, cyano, C₁-C₇ alkyl, C₁-C₇ alkoxy,C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁶⁻¹⁻¹”; R¹⁻⁶⁻¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻⁷ is independently hydrogen, —OR¹⁻⁷⁻¹, —NR¹⁻⁷⁻²R¹⁻⁷⁻³ or“C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻⁷⁻⁴; R¹⁻⁷⁻¹ is independentlyhydrogen, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl; R¹⁻⁷⁻² andR¹⁻⁷⁻³ are independently C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl orC₃-C₁₄ cycloalkyl; or, R¹⁻⁷⁻² and R¹⁻⁷⁻³ together with the nitrogen atomthey are attached to form a C₃-C₁₄ heterocycloalkyl optionallysubstituted by one, two or three R¹⁻⁷⁻²⁻¹; one or more methylenes in theC₃-C₁₄ heterocycloalkyl are optionally and independently substituted byoxygen atom, sulfur atom, sulfinyl, sulfonyl, carbonyl, vinylidene or—N(R¹⁻⁷⁻²⁻²)—; R¹⁻⁷⁻²⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻⁷⁻²⁻² is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;R¹⁻⁷⁻⁴ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇heteroaryl or “amino substituted by one or two R¹⁻⁷⁻⁴⁻¹”; R¹⁻⁷⁻⁴⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁸ is independentlyhalogen, —OH, amino, mercapto, cyano, C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇alkylthio, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁸⁻¹”; R¹⁻⁸⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R² is —OR²⁻¹, cyano, carboxyl; or “C₂-C₇ alkyl, C₃-C₁₄cycloalkyl or C₃-C₁₄ heterocycloalkyl” optionally substituted by one,two or three R²⁻²; R²⁻¹ is C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl,C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇heteroaryl; R²⁻² is independently halogen, hydroxyl, amino, C₁-C₇ alkyl,C₁-C₇ alkoxy, C₃-C₁₄ cycloalkyl or C₃-C₁₄ heterocycloalkyl; in any oneof the above cases, the heteroatoms in the C₃-C₁₄ heterocycloalkyl,C₁-C₇ heteroaryl are independently selected from one or more of boron,silicon, oxygen, sulfur, selenium, nitrogen and phosphorus; the numberof heteroatoms is independently 1, 2, 3 or
 4. 3. The pyrazolone-fusedpyrimidine compound represented by formula II according to claim 1, thepharmaceutically acceptable salt thereof, the solvate thereof, thesolvate of the pharmaceutically acceptable salt thereof, the metabolitethereof or the prodrug thereof, wherein, when A is C₃-C₂₀ cycloalkylsubstituted by one or two R¹, the C₃-C₂₀ cycloalkyl is C₃-C₂₀ monocycliccycloalkyl, C₃-C₂₀ spiro cycloalkyl, C₃-C₂₀ fused cycloalkyl or C₃-C₂₀bridged cycloalkyl; or, when A is C₃-C₂₀ cycloalkyl substituted by oneor two R¹, the C₃-C₂₀ cycloalkyl is C₃-C₂₀ saturated cycloalkyl; or,when R¹ is independently C₃-C₁₄ heterocycloalkyl, the C₃-C₁₄heterocycloalkyl is C₃-C₁₄ monocyclic heterocycloalkyl, C₃-C₁₄ spiroheterocycloalkyl, C₃-C₁₄ fused heterocycloalkyl or C₃-C₁₄ bridgedheterocycloalkyl; or, when R¹ is independently C₃-C₁₄ heterocycloalkyl,the heteroatom of the C₃-C₁₄ heterocycloalkyl is not substituted; or,when R¹ is independently C₃-C₁₄ heterocycloalkyl, the methylene in theC₃-C₁₄ heterocycloalkyl is not substituted; or, when R¹ is independentlyC₃-C₁₄ heterocycloalkyl substituted by one R¹⁻⁸, the C₃-C₁₄heterocycloalkyl is C₃-C₁₄ monocyclic heterocycloalkyl, C₃-C₁₄ spiroheterocycloalkyl, C₃-C₁₄ fused heterocycloalkyl or C₃-C₁₄ bridgedheterocycloalkyl; or, when R¹ is independently C₃-C₁₄ heterocycloalkylsubstituted by one R¹⁻⁸, the heteroatom of the C₃-C₁₄ heterocycloalkylis not substituted except R¹⁻⁸; or, when R¹ is independently C₃-C₁₄heterocycloalkyl substituted by one R¹⁻⁸, the methylene in the C₃-C₁₄heterocycloalkyl is not substituted; or, when R¹⁻³ and R¹⁻⁴ areindependently C₁-C₇ alkyl, the C₁-C₇ alkyl is C₁-C₃ alkyl; or, whenR¹⁻³⁻¹ is independently C₁-C₇ alkyl, the C₁-C₇ alkyl is C₁-C₃ alkyl; or,when R¹⁻³⁻² is independently C₃-C₁₄ cycloalkyl, the C₃-C₁₄ cycloalkyl isC₃-C₁₄ monocyclic cycloalkyl, C₃-C₁₄ spiro cycloalkyl, C₃-C₁₄ fusedcycloalkyl or C₃-C₁₄ bridged cycloalkyl; or, when R¹⁻³⁻² is C₃-C₁₄cycloalkyl, the C₃-C₁₄ cycloalkyl is C₃-C₁₄ saturated cycloalkyl; or,when R¹⁻⁵ is independently C₃-C₁₄ heterocycloalkyl, the C₃-C₁₄heterocycloalkyl is C₃-C₁₄ monocyclic heterocycloalkyl, C₃-C₁₄ spiroheterocycloalkyl, C₃-C₁₄ fused heterocycloalkyl or C₃-C₁₄ bridgedheterocycloalkyl; or, when R¹⁻⁵ is independently C₃-C₁₄heterocycloalkyl, the heteroatom of the C₃-C₁₄ heterocycloalkyl is notsubstituted; or, when R¹⁻⁵ is independently C₃-C₁₄ heterocycloalkyl, themethylene in the C₃-C₁₄ heterocycloalkyl is not substituted; or, whenR¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently C₁-C₇ alkyl, the C₁-C₇ alkyl isC₁-C₃ alkyl; or, when R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently C₃-C₁₄cycloalkyl, the C₃-C₁₄ cycloalkyl is C₃-C₁₄ monocyclic cycloalkyl,C₃-C₁₄ spiro cycloalkyl, C₃-C₁₄ fused cycloalkyl or C₃-C₁₄ bridgedcycloalkyl; or, when R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently C₃-C₁₄cycloalkyl, the C₃-C₁₄ cycloalkyl is C₃-C₁₄ saturated cycloalkyl; or,when R¹⁻⁵⁻³ is independently C₁-C₇ alkyl, the C₁-C₇ alkyl is C₁-C₃alkyl; or, when R¹⁻⁹ is independently C₁-C₇ alkyl, the C₁-C₇ alkyl isC₁-C₃ alkyl; or, when R² is C₂-C₇ alkyl optionally substituted by one,two or three R²⁻², the C₂-C₇ alkyl is C₂-C₄ alkyl; or, when R² is C₃-C₁₄heterocycloalkyl optionally substituted by one, two or three R²-2, theC₃-C₁₄ heterocycloalkyl is C₃-C₁₄ monocyclic heterocycloalkyl, C₃-C₁₄spiro heterocycloalkyl, C₃-C₁₄ fused heterocycloalkyl or C₃-C₁₄ bridgedheterocycloalkyl; or, when R² is C₃-C₁₄ heterocycloalkyl optionallysubstituted by one, two or three R²-2, the heteroatom of the C₃-C₁₄heterocycloalkyl is not substituted except R²⁻²; or, when R² is C₃-C₁₄heterocycloalkyl optionally substituted by one, two or three R²-2, themethylene in the C₃-C₁₄ heterocycloalkyl is not substituted; or, theratio of each isomer in the pyrazolone-fused pyrimidine compoundrepresented by formula II is equal; or, the atoms in thepyrazolone-fused pyrimidine compound represented by formula II, thepharmaceutically acceptable salt thereof, the solvate thereof, thesolvate of the pharmaceutically acceptable salt thereof, the metabolitethereof or the prodrug thereof all exist in their natural abundance. 4.The pyrazolone-fused pyrimidine compound represented by formula IIaccording to claim 3, the pharmaceutically acceptable salt thereof, thesolvate thereof, the solvate of the pharmaceutically acceptable saltthereof, the metabolite thereof or the prodrug thereof, wherein, when Ais C₃-C₂₀ cycloalkyl substituted by one or two R¹, the C₃-C₂₀ cycloalkylis C₃-C₂₀ monocyclic cycloalkyl, C₃-C₂₀ monocyclic cycloalkyl is C₃-C₆monocyclic cycloalkyl; or, when A is C₃-C₂₀ cycloalkyl substituted byone or two R¹, the C₃-C₂₀ cycloalkyl is C₃-C₂₀ bridged cycloalkyl; theC₃-C₂₀ bridged cycloalkyl is C₅-C₈ bridged cycloalkyl; or, when R¹ isindependently C₃-C₁₄ heterocycloalkyl, the C₃-C₁₄ heterocycloalkyl isC₃-C₁₄ monocyclic heterocycloalkyl; the C₃-C₁₄ monocyclicheterocycloalkyl is “C₃-C₉ monocyclic heterocycloalkyl having one or twoheteroatoms selected from one or two of N, O and S”; or, when R¹ isindependently C₃-C₁₄ heterocycloalkyl substituted by one R¹⁻⁸, theC₃-C₁₄ heterocycloalkyl is C₃-C₁₄ monocyclic heterocycloalkyl; theC₃-C₁₄ monocyclic heterocycloalkyl is the “C₃-C₉ monocyclicheterocycloalkyl having one or two heteroatoms selected from one or twoof N, O and S”; or, when R¹⁻³ and R¹⁻⁴ are independently C₁-C₇ alkyl,the C₁-C₇ alkyl is methyl, ethyl, n-propyl or isopropyl; or, when R¹⁻³⁻¹is independently C₁-C₇ alkyl, the C₁-C₇ alkyl is methyl, ethyl, n-propylor isopropyl; or, when R¹⁻³⁻² is independently C₃-C₁₄ cycloalkyl, theC₃-C₁₄ cycloalkyl is C₃-C₁₄ monocyclic cycloalkyl; the C₃-C₁₄ monocycliccycloalkyl is C₃-C₆ monocyclic cycloalkyl; or, when R¹⁻⁵ isindependently C₃-C₁₄ heterocycloalkyl, the C₃-C₁₄ heterocycloalkyl isC₃-C₁₄ monocyclic heterocycloalkyl; the C₃-C₁₄ monocyclicheterocycloalkyl is “C₃-C₉ monocyclic heterocycloalkyl having one or twoheteroatoms selected from one or two of N, O and S”; or, when R¹⁻⁵⁻¹ andR¹⁻⁵⁻² are independently C₁-C₇ alkyl, the C₁-C₇ alkyl is methyl, ethyl,n-propyl or isopropyl; or, when R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independentlyC₃-C₁₄ cycloalkyl, the C₃-C₁₄ cycloalkyl is C₃-C₁₄ monocycliccycloalkyl; the C₃-C₁₄ monocyclic cycloalkyl is C₃-C₆ monocycliccycloalkyl; or, when R¹⁻⁵⁻³ is independently C₁-C₇ alkyl, the C₁-C₇alkyl is methyl, ethyl, n-propyl or isopropyl; or, when R² is C₂-C₇alkyl optionally substituted by one, two or three R²⁻², the C₂-C₇ alkylis ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl ortert-butyl; or, when R² is independently C₃-C₁₄ heterocycloalkylsubstituted by one, two or three R²⁻², the C₃-C₁₄ heterocycloalkyl isC₃-C₁₄ monocyclic heterocycloalkyl; the C₃-C₁₄ monocyclicheterocycloalkyl is “C₃-C₉ monocyclic heterocycloalkyl having one or twoheteroatoms selected from one or two of N, O and S”; or, the ratio ofeach isomer in the pyrazolone-fused pyrimidine compound represented byformula I is equal; or, the atoms in the pyrazolone-fused pyrimidinecompound represented by formula I, the pharmaceutically acceptable saltthereof, the solvate thereof, the solvate of the pharmaceuticallyacceptable salt thereof, the metabolite thereof or the prodrug thereofall exist in their natural abundance.
 5. The pyrazolone-fused pyrimidinecompound represented by formula II according to claim 4, thepharmaceutically acceptable salt thereof, the solvate thereof, thesolvate of the pharmaceutically acceptable salt thereof, the metabolitethereof or the prodrug thereof, wherein, when A is C₃-C₂₀ cycloalkylsubstituted by one or two R¹, the C₃-C₂₀ cycloalkyl is C₃-C₂₀ monocycliccycloalkyl, the C₃-C₂₀ monocyclic cycloalkyl is cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl; or, when A is C₃-C₂₀ cycloalkyl substitutedby one or two R¹, the C₃-C₂₀ cycloalkyl is C₃-C₂₀ bridged cycloalkyl;the C₃-C₂₀ bridged cycloalkyl is

or, when R¹ is independently C₃-C₁₄ heterocycloalkyl, the C₃-C₁₄heterocycloalkyl is C₃-C₁₄ monocyclic heterocycloalkyl; the C₃-C₁₄monocyclic heterocycloalkyl is

or, when R¹ is independently C₃-C₁₄ heterocycloalkyl substituted by oneR¹⁻⁸, the C₃-C₁₄ heterocycloalkyl substituted by one R¹⁻⁸ is;

or, when R¹⁻³⁻² is C₃-C₁₄ cycloalkyl, the C₃-C₁₄ cycloalkyl is C₃-C₁₄monocyclic cycloalkyl; the C₃-C₁₄ monocyclic cycloalkyl is cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl; or, when R¹⁻⁵ is independentlyC₃-C₁₄ heterocycloalkyl, the C₃-C₁₄ heterocycloalkyl is C₃-C₁₄monocyclic heterocycloalkyl; the C₃-C₁₄ monocyclic heterocycloalkyl is

or, when R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently C₃-C₁₄ cycloalkyl, theC₃-C₁₄ cycloalkyl is C₃-C₁₄ monocyclic cycloalkyl; the C₃-C₁₄ monocycliccycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or,when R² is C₃-C₁₄ heterocycloalkyl optionally substituted by one, two orthree R²⁻², the C₃-C₁₄ heterocycloalkyl is C₃-C₁₄ monocyclicheterocycloalkyl; the C₃-C₁₄ monocyclic heterocycloalkyl is oxetan-3-yl.6. The pyrazolone-fused pyrimidine compound represented by formula IIaccording to claim 1, the pharmaceutically acceptable salt thereof, thesolvate thereof, the solvate of the pharmaceutically acceptable saltthereof, the metabolite thereof or the prodrug thereof, wherein, when Ais C₃-C₂₀ cycloalkyl substituted by one R¹, the A is

or, when R¹ is independently C₃-C₁₄ heterocycloalkyl, the C₃-C₁₄heterocycloalkyl is C₃-C₁₄ monocyclic heterocycloalkyl; the C₃-C₁₄monocyclic heterocycloalkyl is

or, when R¹⁻⁵ is independently C₃-C₁₄ heterocycloalkyl, the C₃-C₁₄heterocycloalkyl is C₃-C₁₄ monocyclic heterocycloalkyl; the C₃-C₁₄monocyclic heterocycloalkyl

or, when R² is C₂-C₇ alkyl substituted by one R²⁻², R²⁻² is hydroxyl;the C₂-C₇ alkyl substituted by one R²⁻² is

or, when R² is C₃-C₁₄ heterocycloalkyl substituted by one R²⁻², R²⁻² ishalogen or hydroxyl; the C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²is


7. The pyrazolone-fused pyrimidine compound represented by formula IIaccording to claim 6, the pharmaceutically acceptable salt thereof, thesolvate thereof, the solvate of the pharmaceutically acceptable saltthereof, the metabolite thereof or the prodrug thereof, wherein, when Ais C₃-C₂₀ cycloalkyl substituted by one R¹; the A is


8. The pyrazolone-fused pyrimidine compound represented by formula IIaccording to claim 1, the pharmaceutically acceptable salt thereof, thesolvate thereof, the solvate of the pharmaceutically acceptable saltthereof, the metabolite thereof or the prodrug thereof, wherein, A isC₃-C₂₀ cycloalkyl substituted by one R¹; or, X is N; or, R¹ isindependently cyano, halogen, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, —C(═NR¹⁻⁶)R¹⁻⁷,═N—O—R¹⁻⁹, C₁-C₇ heteroaryl or “C₃-C₁₄ heterocycloalkyl” optionallysubstituted by one R¹⁻⁸; or, R¹⁻³ and R¹⁻⁴ are independently hydrogen,—S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻², —C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶, or C₁-C₇ alkyl;R¹⁻³⁻¹ and R¹⁻³⁻² are independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;R¹⁻³⁻³ is hydrogen; R¹⁻³⁻⁵ and R¹⁻³⁻⁶ are hydrogen; or, R¹⁻⁵ isindependently —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄ heterocycloalkyl;R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻⁵⁻³ is independently hydrogen or C₁-C₇ alkyl; or, R¹⁻⁸ isindependently oxo; or, R² is “C₂-C₇ alkyl, C₃-C₁₄ cycloalkyl or C₃-C₁₄heterocycloalkyl” optionally substituted by one, two or three R²⁻²; R²⁻²is independently halogen or hydroxyl.
 9. The pyrazolone-fused pyrimidinecompound represented by formula II according to claim 1, thepharmaceutically acceptable salt thereof, the solvate thereof, thesolvate of the pharmaceutically acceptable salt thereof, the metabolitethereof or the prodrug thereof, wherein, A is C₃-C₂₀ cycloalkylsubstituted by one R¹; or, R¹ is independently cyano, halogen,—NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, —C(═NR¹⁻⁶)R¹⁻⁷, C₁-C₇ heteroaryl or C₃-C₁₄heterocycloalkyl; or, R¹⁻³ and R¹⁻⁴ are independently hydrogen,—S(═O)₂R¹⁻³⁻¹ or C₁-C₇ alkyl; R¹⁻³⁻¹ is independently C₁-C₇ alkyl; or,R¹⁻⁵ is independently —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄heterocycloalkyl; R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ is independently hydrogen or C₁-C₇alkyl; or, R² is “C₂-C₇ alkyl, C₃-C₁₄ cycloalkyl or C₃-C₁₄heterocycloalkyl” optionally substituted by one, two or three R²⁻²; R²⁻²is independently halogen or hydroxyl.
 10. The pyrazolone-fusedpyrimidine compound represented by formula II according to claim 9, thepharmaceutically acceptable salt thereof, the solvate thereof, thesolvate of the pharmaceutically acceptable salt thereof, the metabolitethereof or the prodrug thereof, wherein, R¹ is independently —NR¹⁻³R¹⁻⁴,—C(═O)R¹⁻⁵ or C₃-C₁₄ heterocycloalkyl; or, R¹⁻⁵ is independently—NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄ heterocycloalkyl; R¹⁻⁵⁻¹ and R¹⁻⁵⁻²are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ ishydrogen; or, R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substitutedby one R²⁻²”; R²⁻² is halogen or hydroxyl.
 11. The pyrazolone-fusedpyrimidine compound represented by formula II according to claim 1, thepharmaceutically acceptable salt thereof, the solvate thereof, thesolvate of the pharmaceutically acceptable salt thereof, the metabolitethereof or the prodrug thereof, wherein, the pyrazolone-fused pyrimidinecompound represented by formula II is any of the following schemes:scheme (1):

A is

substituted by one or two R¹; R¹ is independently halogen, —CN,—NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, —C(═NR¹⁻⁶)R¹⁻⁷ or “C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇ heteroaryl” optionallysubstituted by one, two or three R¹⁻⁸; R¹⁻³ and R¹⁻⁴ are independentlyhydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻², —C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶,—S(═O)₂NR¹⁻³⁻⁷R¹⁻³⁻⁸, —C(═O)NR¹⁻³⁻⁹R¹⁻³⁻¹⁰ or “C₁-C₇ alkyl, C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl”optionally substituted by one, two or three R¹⁻³⁻¹¹; R¹⁻³⁻¹ and R¹⁻³⁻²are independently “C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl or C₆-C₁₀ aryl” optionally substituted by one or twoR¹⁻³⁻¹⁻¹; R¹⁻³⁻¹⁻¹ is independently C₁-C₇ alkyl; R¹⁻³⁻³ is independentlyhydrogen; R¹⁻³⁻⁵, R¹⁻³⁻⁶, R¹⁻³⁻⁷, R¹⁻³⁻⁸, R¹⁻³⁻⁹ and R¹⁻³⁻¹⁰ areindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻³⁻¹¹ is independentlyhalogen, hydroxyl, amino, mercapto, cyano, C₁-C₇ alkyl, C₁-C₇ alkoxy,C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀aryl, C₁-C₇ heteroaryl or “amino substituted by one or two R¹⁻³⁻¹¹”;R¹⁻³⁻¹¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵ isindependently hydrogen, —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or “C₁-C₇ alkyl, C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl”optionally substituted by one, two or three R¹⁻⁵⁻⁴; R¹⁻⁵⁻¹ and R¹⁻⁵⁻²are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ isindependently hydrogen, C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl; R¹⁻⁵⁻⁴ isindependently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇ alkyl,C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁵⁻⁴⁻¹”; R¹⁻⁵⁻⁴⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻⁶ is independently hydrogen, —CN, —OH; R¹⁻⁷ isindependently hydrogen, —NR¹⁻⁷⁻²R¹⁻⁷⁻³; R¹⁻⁷⁻² and R¹⁻⁷⁻³ areindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; or, R¹⁻⁷⁻² and R¹⁻⁷⁻³together with the nitrogen atom they are attached to form a C₃-C₁₄heterocycloalkyl optionally substituted by one, two or three R¹⁻⁷⁻²⁻¹;one or more methylenes in the C₃-C₁₄ heterocycloalkyl are optionally andindependently substituted by oxygen atom, sulfur atom; R¹⁻⁷⁻²⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁸ is independentlyhalogen, —OH, amino, mercapto, cyano, C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl,C₁-C₇ heteroaryl or “amino substituted by one or two R¹⁻⁸⁻¹”; R¹⁻⁸⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R² is “C₂-C₇ alkyl,C₃-C₁₄ cycloalkyl or C₃-C₁₄ heterocycloalkyl” optionally substituted byone, two or three R²⁻²; R²⁻² is independently halogen or hydroxyl; inany one of the above cases, the heteroatoms in the C₃-C₁₄heterocycloalkyl, C₁-C₇ heteroaryl are independently selected from oneor more of boron, silicon, oxygen, sulfur, selenium, nitrogen andphosphorus; the number of heteroatoms is independently 1, 2, 3 or 4;scheme (2):

A is C₃-C₂₀ cycloalkyl substituted by one or two R¹; R¹ is independentlycyano, halogen, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, —C(═NR¹⁻⁶)R¹⁻⁷, C₁-C₇ heteroarylor C₃-C₁₄ heterocycloalkyl; R¹⁻³ and R¹⁻⁴ are independently hydrogen,—S(═O)₂R¹⁻³⁻¹ or C₁-C₇ alkyl; R¹⁻³⁻¹ is independently C₁-C₇ alkyl; R¹⁻⁵is independently —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄ heterocycloalkyl;R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻⁵⁻³ is independently hydrogen or C₁-C₇ alkyl; R² is“C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”; R²⁻²is halogen or hydroxyl; scheme (3):

A is C₃-C₂₀ cycloalkyl substituted by one R¹; R¹ is —NR¹⁻³R¹⁻⁴,—C(═O)R¹⁻⁵ or C₃-C₁₄ heterocycloalkyl; R¹⁻³ and R¹⁻⁴ are independentlyhydrogen, —S(═O)₂R¹⁻³⁻¹ or C₁-C₇ alkyl; R¹⁻³⁻¹ is independently C₁-C₇alkyl; R¹⁻⁵ is —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄ heterocycloalkyl;R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻⁵⁻³ is hydrogen or C₁-C₇ alkyl; R² is “C₂-C₇ alkyl orC₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”; R²⁻² is hydroxyl;scheme (4):

A is C₃-C₂₀ cycloalkyl substituted by one R¹; R¹ is —NR¹⁻³R¹⁻⁴,—C(═O)R¹⁻⁵ or C₃-C₁₄ heterocycloalkyl; R¹⁻³ and R¹⁻⁴ are independentlyhydrogen, —S(═O)₂R¹⁻³⁻¹ or C₁-C₇ alkyl; R¹⁻³⁻¹ is independently C₁-C₇alkyl; R¹⁻⁵ is —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄ heterocycloalkyl;R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻⁵⁻³ is hydrogen; R² is “C₂-C₇ alkyl or C₃-C₁₄heterocycloalkyl substituted by one R²⁻²”; R²⁻² is hydroxyl; scheme (5):

A is

R¹ is —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵ or C₃-C₁₄ heterocycloalkyl; R¹⁻³ and R¹⁻⁴are independently hydrogen, —S(═O)₂R¹⁻³⁻¹ or C₁-C₇ alkyl; R¹⁻³⁻¹ isindependently C₁-C₇ alkyl; R¹⁻⁵ is —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄heterocycloalkyl; R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ is hydrogen or C₁-C₇ alkyl; R² is“C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”; R²⁻²is hydroxyl; scheme (6):

A is

R¹ is —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵ or C₃-C₁₄ heterocycloalkyl; R¹⁻³ and R¹⁻⁴are independently hydrogen, —S(═O)₂R¹⁻³⁻¹ or C₁-C₇ alkyl; R¹⁻³⁻¹ isindependently C₁-C₇ alkyl; R¹⁻⁵ is —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄heterocycloalkyl; R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ is hydrogen or C₁-C₇ alkyl; R² is

scheme (7): A is

substituted by one or two R¹; X is CH or N; R¹ is independently halogen,—CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, —C(═NR¹⁻⁶)R¹⁻⁷, ═N—O—R¹⁻⁹ or “C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl, or C₁-C₇ heteroaryl”optionally substituted by one, two or three R¹⁻⁸; R¹⁻³ and R¹⁻⁴ areindependently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶, —S(═O)₂NR¹⁻³⁻⁷R¹⁻³⁻⁸, —C(═O)NR¹⁻³⁻⁹R¹⁻³⁻¹⁰ or“C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl orC₁-C₇ heteroaryl” optionally substituted by one, two or three R¹⁻³⁻¹¹;R¹⁻³⁻¹ and R¹⁻³⁻² are independently “C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl,C₃-C₁₄ heterocycloalkyl or C₆-C₁₀ aryl optionally substituted” by one ortwo R¹⁻³⁻¹⁻¹; R¹⁻³⁻¹⁻¹ is independently C₁-C₇ alkyl; R¹⁻³⁻³ isindependently hydrogen; R¹⁻³⁻⁵, R¹⁻³⁻⁶, R¹⁻³⁻⁷, R¹⁻³⁻⁸, R¹⁻³⁻⁹ andR¹⁻³⁻¹⁰ are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl;R¹⁻³⁻¹¹ is independently halogen, hydroxyl, amino, mercapto, cyano,C₁-C₇ alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻³⁻¹¹”; R¹⁻³⁻¹¹⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻⁵ is independently hydrogen, —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or“C₁-C₇ alkyl, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl orC₁-C₇ heteroaryl” optionally substituted by one, two or three R¹⁻⁵⁻⁴;R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻⁵⁻³ is independently hydrogen, C₁-C₇ alkyl, C₃-C₁₄cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀ aryl or C₁-C₇ heteroaryl;R¹⁻⁵⁻⁴ is independently halogen, hydroxyl, amino, mercapto, cyano, C₁-C₇alkyl, C₁-C₇ alkoxy, C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄heterocycloalkyl, C₆-C₁₀ aryl, C₁-C₇ heteroaryl or “amino substituted byone or two R¹⁻⁵⁻⁴⁻¹”; R¹⁻⁵⁻⁴⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻⁶ is independently hydrogen, —CN, —OH; R¹⁻⁷ isindependently hydrogen, —NR¹⁻⁷⁻²R¹⁻⁷⁻³; R¹⁻⁷⁻² and R¹⁻⁷⁻³ areindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; or, R¹⁻⁷⁻² and R¹⁻⁷⁻³together with the nitrogen atom they are attached to form a C₃-C₁₄heterocycloalkyl optionally substituted by one, two or three R¹⁻⁷⁻²⁻¹;one or more methylenes in the C₃-C₁₄ heterocycloalkyl are optionally andindependently substituted by oxygen atom, sulfur atom; R¹⁻⁷⁻²⁻¹ isindependently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁸ is independentlyoxo, halogen, —OH, amino, mercapto, cyano, C₁-C₇ alkyl, C₁-C₇ alkoxy,C₁-C₇ alkylthio, C₃-C₁₄ cycloalkyl, C₃-C₁₄ heterocycloalkyl, C₆-C₁₀aryl, C₁-C₇ heteroaryl or “amino substituted by one or two R¹⁻⁸⁻¹”;R¹⁻⁸⁻¹ is independently C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁹ isindependently hydrogen or C₁-C₇ alkyl; R² is “C₂-C₇ alkyl, C₃-C₁₄cycloalkyl or C₃-C₁₄ heterocycloalkyl” optionally substituted by one,two or three R²⁻²; R²⁻² is independently halogen or hydroxyl; in any oneof the above cases, the heteroatoms in the C₃-C₁₄ heterocycloalkyl,C₁-C₇ heteroaryl are independently selected from one or more of boron,silicon, oxygen, sulfur, selenium, nitrogen and phosphorus; the numberof heteroatoms is independently 1, 2, 3 or 4; scheme (8): A is C₃-C₂₀cycloalkyl substituted by one or two R¹; X is CH or N; R¹ isindependently cyano, halogen, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, —C(═NR¹⁻⁶)R¹⁻⁷,═N—O—R¹⁻⁹, C₁-C₇ heteroaryl or “C₃-C₁₄ heterocycloalkyl” optionallysubstituted by one R¹⁻⁸; R¹⁻³ and R¹⁻⁴ are independently hydrogen,—S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻², —C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶, or C₁-C₇ alkyl;R¹⁻³⁻¹ and R¹⁻³⁻² are independently C₁-C₇ alkyl, or C₃-C₁₄ cycloalkyl;R¹⁻³⁻³ is hydrogen; R¹⁻³⁻⁵ and R¹⁻³⁻⁶ are hydrogen; R¹⁻⁵ isindependently —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄ heterocycloalkyl;R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄cycloalkyl; R¹⁻⁵⁻³ is independently hydrogen or C₁-C₇ alkyl; R¹⁻⁸ isindependently oxo; R¹⁻⁹ is independently hydrogen or C₁-C₇ alkyl; R² is“C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by one R²⁻²”; R²⁻²is halogen or hydroxyl; scheme (9): A is C₃-C₂₀ cycloalkyl substitutedby one R¹; X is CH or N; R¹ is —CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, ═N—O—R¹⁻⁹ or“C₃-C₁₄ heterocycloalkyl” optionally substituted by one R¹⁻⁸; R¹⁻³ andR¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶ or C₁-C₇ alkyl; R¹⁻³⁻¹ and R¹⁻³⁻² areindependently C₁-C₇ alkyl, or C₃-C₁₄ cycloalkyl; R¹⁻³⁻³ is hydrogen;R¹⁻³⁻⁵ and R¹⁻³⁻⁶ are hydrogen; R¹⁻⁵ is —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ orC₃-C₁₄ heterocycloalkyl; R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen,C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ is independently hydrogen orC₁-C₇ alkyl; R¹⁻⁸ is independently oxo; R¹⁻⁹ is independently hydrogenor C₁-C₇ alkyl; R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkylsubstituted by one R²⁻²”; R²⁻² is hydroxyl; scheme (10): A is C₃-C₂₀cycloalkyl substituted by one R¹; X is CH or N; R¹ is —CN, —NR¹⁻³R¹⁻⁴,—C(═O)R¹⁻⁵, ═N—O—R¹⁻⁹, or “C₃-C₁₄ heterocycloalkyl” optionallysubstituted by one R¹⁻⁸; R¹⁻³ and R¹⁻⁴ are independently hydrogen,—S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻², —C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶, or C₁-C₇ alkyl;R¹⁻³⁻¹ and R¹⁻³⁻² are independently C₁-C₇ alkyl, or C₃-C₁₄ cycloalkyl;R¹⁻³⁻³ is hydrogen; R¹⁻³⁻⁵ and R¹⁻³⁻⁶ are hydrogen; R¹⁻⁵ is—NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ or C₃-C₁₄ heterocycloalkyl; R¹⁻⁵⁻¹ and R¹⁻⁵⁻²are independently hydrogen, C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ ishydrogen; R¹⁻⁸ is independently oxo; R¹⁻⁹ is independently hydrogen orC₁-C₇ alkyl; R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substitutedby one R²⁻²”; R²⁻² is hydroxyl; scheme (11): A is R or R

X is CH or N; R¹ is —CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵, ═N—O—R¹⁻⁹, or “C₃-C₁₄heterocycloalkyl” optionally substituted by one R¹⁻⁸; R¹⁻³ and R¹⁻⁴ areindependently hydrogen, —S(═O)₂R¹⁻³⁻¹, —C(═O)R¹⁻³⁻²,—C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶ or C₁-C₇ alkyl; R¹⁻³⁻¹ and R¹⁻³⁻² areindependently C₁-C₇ alkyl, or C₃-C₁₄ cycloalkyl; R¹⁻³⁻³ is hydrogen;R¹⁻³⁻⁵ and R¹⁻³⁻⁶ are hydrogen; R¹⁻⁵ is —NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³ orC₃-C₁₄ heterocycloalkyl; R¹⁻⁵⁻¹ and R¹⁻⁵⁻² are independently hydrogen,C₁-C₇ alkyl or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ is hydrogen or C₁-C₇ alkyl;R¹⁻⁸ is independently oxo; R¹⁻⁹ is independently hydrogen or C₁-C₇alkyl; R² is “C₂-C₇ alkyl or C₃-C₁₄ heterocycloalkyl substituted by oneR²⁻²”; R²⁻² is hydroxyl; scheme (12): A is

X is CH or N; R¹ is independently —CN, —NR¹⁻³R¹⁻⁴, —C(═O)R¹⁻⁵,═N—O—R¹⁻⁹, or “C₃-C₁₄ heterocycloalkyl” optionally substituted by oneR¹⁻⁸; R¹⁻³ and R¹⁻⁴ are independently hydrogen, —S(═O)₂R¹⁻³⁻¹,—C(═O)R¹⁻³⁻², —C(═NR¹⁻³⁻³)NR¹⁻³⁻⁵R¹⁻³⁻⁶ or C₁-C₇ alkyl; R¹⁻³⁻¹ andR¹⁻³⁻² are independently C₁-C₇ alkyl, or C₃-C₁₄ cycloalkyl; R¹⁻³⁻³ ishydrogen; R¹⁻³⁻⁵ and R¹⁻³⁻⁶ are hydrogen; R¹⁻⁵ is independently—NR¹⁻⁵⁻¹R¹⁻⁵⁻², —OR¹⁻⁵⁻³, or C₃-C₁₄ heterocycloalkyl; R¹⁻⁵⁻¹ and R¹⁻⁵⁻²are independently hydrogen, C₁-C₇ alkyl, or C₃-C₁₄ cycloalkyl; R¹⁻⁵⁻³ isindependently hydrogen or C₁-C₇ alkyl; R¹⁻⁸ is independently oxo; R¹⁻⁹is independently hydrogen or C₁-C₇ alkyl; R² is


12. The pyrazolone-fused pyrimidine compound represented by formula IIaccording to claim 1, the pharmaceutically acceptable salt thereof, thesolvate thereof, the solvate of the pharmaceutically acceptable saltthereof, the metabolite thereof or the prodrug thereof, wherein, thepyrazolone-fused pyrimidine compound represented by formula II is any ofthe compounds described in any of the following schemes: scheme A:

scheme B:

its ¹H NMR (400 MHz, MeOD) is δ 8.85 (s, 1H), 8.00 (t, J=7.9 Hz, 1H),7.80 (d, J=8.1 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.62 (d, J=8.6 Hz, 2H),7.28 (d, J=8.6 Hz, 2H), 5.78-5.68 (m, 1H), 5.06 (d, J=10.3 Hz, 1H), 4.95(s, 1H), 4.82 (s, 2H), 3.82-3.76 (m, 1H), 2.81 (s, 1H), 2.71 (s, 3H),2.49 (s, 1H), 2.08 (d, J=10.9 Hz, 3H), 1.94 (d, J=15.0 Hz, 3H), 1.72 (s,4H), 1.59 (d, J=7.0 Hz, 6H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.87 (d, J=2.1 Hz, 1H), 7.91 (td,J=7.9, 1.5 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.54 (t, J=7.9 Hz, 2H), 7.39(d, J=7.7 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 5.72 (ddt, J=16.4, 10.2, 6.2Hz, 1H), 5.07 (dd, J=10.2, 1.1 Hz, 1H), 4.96 (dd, J=17.1, 1.2 Hz, 1H),4.77 (d, J=6.2 Hz, 2H), 4.25-4.10 (m, 2H), 3.95 (s, 1H), 2.73 (s, 1H),2.56 (dt, J=15.5, 10.8 Hz, 1H), 2.28 (d, J=7.9 Hz, 1H), 2.14 (d, J=10.6Hz, 1H), 2.05-1.97 (m, 1H), 1.78 (dd, J=19.0, 8.5 Hz, 1H), 1.67 (dt,J=10.1, 6.1 Hz, 3H), 1.61 (s, 6H), 1.59-1.44 (m, 1H), 1.34-1.26 (m, 3H);

its ¹H NMR (400 MHz, MeOD) is δ 8.84 (d, J=1.4 Hz, 1H), 8.00 (td, J=7.9,4.0 Hz, 1H), 7.83-7.76 (m, 1H), 7.67 (dd, J=7.7, 0.7 Hz, 1H), 7.60 (dd,J=8.4, 5.7 Hz, 2H), 7.19 (dd, J=13.2, 8.6 Hz, 2H), 5.73 (ddd, J=17.0,6.1, 4.1 Hz, 1H), 5.08-5.03 (m, 1H), 4.95 (d, J=1.3 Hz, 1H), 4.86-4.79(m, 2H), 2.72 (s, 1H), 2.58 (s, 1H), 2.27 (d, J=6.7 Hz, 1H), 2.13 (d,J=10.0 Hz, 1H), 1.96 (d, J=10.2 Hz, 1H), 1.80-1.66 (m, 4H), 1.64-1.52(m, 7H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.86 (d, J=4.2 Hz, 1H), 7.97-7.88 (m,1H), 7.79 (d, J=8.0 Hz, 1H), 7.53 (dd, J=12.3, 8.5 Hz, 2H), 7.39 (d,J=7.6 Hz, 1H), 7.28-7.15 (m, 2H), 5.80-5.65 (m, 1H), 5.06 (d, J=10.0 Hz,1H), 4.95 (d, J=17.1 Hz, 1H), 4.77 (d, J=6.0 Hz, 2H), 3.10 (d, J=12.1Hz, 3H), 2.98 (s, 3H), 2.67-2.57 (m, 1H), 2.14 (dd, J=20.9, 10.3 Hz,1H), 2.06-1.97 (m, 2H), 1.92 (d, J=14.0 Hz, 1H), 1.78-1.66 (m, 4H), 1.61(s, 6H), 1.49 (dd, J=22.8, 12.2 Hz, 1H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.85 (d, J=4.7 Hz, 1H), 7.91 (dt,J=10.7, 7.9 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.53 (dd, J=12.0, 8.5 Hz,2H), 7.39 (dd, J=7.6, 2.4 Hz, 1H), 7.22 (dd, J=19.5, 8.5 Hz, 2H), 5.71(ddt, J=16.4, 10.2, 6.2 Hz, 1H), 5.06 (d, J=10.2 Hz, 1H), 4.95 (d,J=17.1 Hz, 1H), 4.77 (d, J=6.1 Hz, 2H), 4.21 (dd, J=16.4, 8.6 Hz, 2H),4.10-4.02 (m, 2H), 2.63-2.52 (m, 2H), 2.35-2.20 (m, 2H), 2.15-2.07 (m,1H), 2.00 (dd, J=13.4, 3.0 Hz, 2H), 1.92-1.83 (m, 1H), 1.79-1.63 (m,4H), 1.60 (s, 6H), 1.48 (ddd, J=24.7, 12.5, 2.5 Hz, 1H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.86 (s, 1H), 7.93-7.85 (m, 1H), 7.78(d, J=7.8 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.39 (dd, J=7.6, 0.7 Hz, 1H),7.19 (d, J=8.5 Hz, 2H), 5.71 (ddt, J=16.4, 10.2, 6.2 Hz, 1H), 5.05 (dd,J=10.2, 1.1 Hz, 1H), 4.94 (dd, J=17.1, 1.3 Hz, 1H), 4.77 (d, J=6.2 Hz,2H), 4.11 (d, J=8.9 Hz, 1H), 3.24 (t, J=7.0 Hz, 4H), 2.52-2.43 (m, 1H),2.14-2.00 (m, 3H), 1.92 (d, J=11.2 Hz, 4H), 1.60 (s, 6H), 1.45 (dt,J=14.9, 7.5 Hz, 2H), 1.23-1.08 (m, 2H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.84 (d, J=3.7 Hz, 1H), 7.94 (dd,J=14.8, 6.9 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.58-7.50 (m, 2H), 7.42(dd, J=7.5, 4.1 Hz, 1H), 7.22 (dd, J=15.8, 8.5 Hz, 2H), 5.71 (dd,J=11.5, 5.4 Hz, 2H), 5.07 (d, J=10.2 Hz, 1H), 4.95 (d, J=17.1 Hz, 1H),4.77 (d, J=6.1 Hz, 2H), 2.82-2.72 (m, 1H), 2.60 (s, 1H), 2.12-2.01 (m,3H), 1.92 (d, J=12.5 Hz, 1H), 1.81-1.67 (m, 3H), 1.62 (s, 6H), 1.54-1.43(m, 1H), 0.93-0.78 (m, 3H), 0.52 (s, 2H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.88 (s, 1H), 7.91 (t, J=7.9 Hz, 1H),7.77 (d, J=7.9 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.40 (d, J=7.4 Hz, 1H),7.19 (d, J=8.5 Hz, 2H), 5.78-5.66 (m, 1H), 5.07 (dd, J=10.2, 1.0 Hz,1H), 4.96 (dd, J=17.1, 1.2 Hz, 1H), 4.77 (d, J=6.2 Hz, 2H), 4.42 (d,J=7.6 Hz, 1H), 3.49-3.35 (m, 1H), 3.04 (s, 3H), 2.57-2.46 (m, 1H),2.29-2.17 (m, 2H), 2.05-1.96 (m, 8H), 1.56-1.65 (m, 2H), 1.41-1.50 (m,2H);

its ¹H NMR (400 MHz, MeOD) is δ 8.84 (s, 1H), 8.02 (m, 1H), 7.80 (m,1H), 7.72-7.58 (m, 3H), 7.25 (m, 2H), 5.73 (ddt, J=16.5, 10.3, 6.1 Hz,1H), 5.05 (dd, J=10.2, 1.0 Hz, 1H), 4.95 (d, 1H), 4.83 (d, J=6.1 Hz,2H), 3.54-3.42 (m, 1H), 2.59 (m, 1H), 2.14 (m, 1H), 1.98 (m, 2H), 1.83(m, 1H), 1.68 (m, 2H), 1.60 (s, 6H), 1.50 (m, 2H);

its ¹H NMR (400 MHz, DMSO) is δ 10.28 (s, 1H), 8.88 (d, J=1.8 Hz, 1H),8.09-7.97 (m, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.66 (dd, J=20.6, 8.5 Hz,3H), 7.19 (dd, J=11.1, 8.7 Hz, 2H), 5.74-5.61 (m, 1H), 5.00 (d, J=10.2Hz, 1H), 4.82 (d, J=17.1 Hz, 1H), 4.69 (d, J=5.5 Hz, 2H), 3.23 (s, 1H),2.74 (t, J=12.1 Hz, 1H), 2.53 (s, 1H), 2.12 (d, J=10.1 Hz, 1H), 1.98 (d,J=13.2 Hz, 1H), 1.82 (d, J=13.2 Hz, 2H), 1.77-1.57 (m, 3H), 1.49 (d,J=18.2 Hz, 6H);

its ¹H NMR (400 MHz, DMSO) is δ 10.27 (s, 1H), 8.89 (s, 1H), 8.12 (s,1H), 7.74 (dd, J=22.6, 8.3 Hz, 3H), 7.64 (d, J=7.3 Hz, 1H), 7.37 (d,J=8.5 Hz, 2H), 5.76-5.61 (m, 1H), 5.34 (s, 1H), 5.01 (dd, J=10.3, 1.2Hz, 1H), 4.84 (d, J=17.1 Hz, 1H), 4.70 (d, J=5.7 Hz, 2H), 3.62 (s, 1H),3.12 (s, 1H), 2.71-2.58 (m, 8H), 2.38 (d, J=9.2 Hz, 2H), 1.47 (s, 6H),1.32-1.24 (m, 1H);

its ¹H NMR (400 MHz, DMSO) is δ 10.26 (s, 1H), 8.88 (s, 1H), 8.07 (t,J=7.8 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.65 (dd, J=14.5, 7.9 Hz, 2H),7.22 (d, J=8.5 Hz, 2H), 5.74-5.60 (m, 1H), 5.35 (s, 1H), 5.00 (d, J=10.3Hz, 1H), 4.83 (d, J=17.1 Hz, 1H), 4.69 (d, J=5.6 Hz, 2H), 3.74 (s, 3H),3.24-3.15 (m, 1H), 2.77 (t, J=12.0 Hz, 1H), 2.37 (d, J=14.0 Hz, 1H),2.25 (td, J=13.4, 4.6 Hz, 1H), 1.99-1.84 (m, 3H), 1.67-1.50 (m, 2H),1.49 (d, J=14.0 Hz, 6H);

its ¹H NMR (400 MHz, MeOD) is δ 8.86 (s, 0H), 8.11-8.01 (m, 1H), 7.94(d, J=7.9 Hz, 2H), 7.67 (d, J=7.6 Hz, 2H), 7.62 (d, J=8.6 Hz, 2H), 7.28(d, J=8.5 Hz, 2H), 5.83-5.74 (m, 1H), 5.09 (dd, J=7.9, 4.4 Hz, 3H), 4.98(dd, J=17.1, 1.3 Hz, 2H), 4.85 (d, J=6.7 Hz, 2H), 2.87 (s, 1H), 2.64 (s,1H), 2.47 (s, 3H), 1.97-1.67 (m, 8H);

its ¹H NMR (400 MHz, MeOD) is δ 8.87 (d, J=6.6 Hz, 1H), 8.06 (t, J=7.9Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.68 (dd, J=7.8, 5.4 Hz, 2H), 7.61 (d,J=8.6 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.24 (t, J=8.7 Hz, 1H), 5.84-5.72(m, 1H), 5.09 (d, J=6.2 Hz, 2H), 5.07 (d, J=1.3 Hz, 1H), 5.02-4.94 (m,2H), 4.90 (s, 2H), 4.84 (d, J=6.7 Hz, 2H), 3.15 (d, J=2.6 Hz, 1H), 3.08(s, 1H), 2.95 (s, 1H), 2.71 (s, 1H), 2.43 (s, 1H), 1.93-2.03 (m, 3H),1.76 (s, 2H), 1.51 (s, 1H), 1.31 (d, J=4.3 Hz, 3H), 0.89 (dd, J=20.1,9.0 Hz, 4H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.87-8.79 (m, 1H), 8.14-8.07 (m, 1H),8.04-7.96 (m, 1H), 7.89-7.80 (m, 1H), 7.61-7.50 (m, 2H), 7.38-7.32 (m,1H), 7.25-7.19 (m, 1H), 7.01 (t, J=3.4 Hz, 1H), 5.72 (ddd, J=16.6, 11.1,8.6 Hz, 1H), 5.17-5.09 (m, 2H), 5.04-4.98 (m, 1H), 4.98-4.92 (m, 1H),4.87-4.77 (m, 2H), 4.73-4.64 (m, 2H), 4.20-4.06 (m, 1H), 3.47-3.38 (m,1H), 3.38-3.29 (m, 1H), 3.05-2.98 (m, 1H), 2.49-2.35 (m, 2H), 2.27-2.17(m, 1H), 2.07-1.86 (m, 4H), 1.75-1.60 (m, 3H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.77 (s, 1H), 8.16-8.07 (m, 1H), 8.03(d, J=7.6 Hz, 1H), 7.83-7.75 (m, 1H), 7.56 (dd, J=12.6, 6.1 Hz, 2H),7.33 (d, J=8.5 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 5.72 (dd, J=17.0, 10.3Hz, 1H), 5.13 (dd, J=9.1, 6.1 Hz, 2H), 4.96 (d, J=17.0 Hz, 2H), 4.81 (d,J=7.2 Hz, 2H), 4.69 (d, J=6.2 Hz, 2H), 4.41-4.28 (m, 2H), 3.86 (s, 1H),3.77 (t, J=6.6 Hz, 1H), 3.63-3.50 (m, 2H), 2.98 (m, 1H), 2.15 (m, 1H),1.97 (dd, J=18.9, 9.6 Hz, 2H), 1.78 (d, J=5.0 Hz, 2H), 1.65 (d, J=8.7Hz, 2H);

its ¹H NMR (400 MHz, CDCl₃) is δ 8.69 (s, 1H), 8.18 (d, J=8.0 Hz, 1H),8.10 (dd, J=17.9, 7.6 Hz, 1H), 7.81-7.72 (m, 1H), 7.63-7.49 (m, 2H),7.25 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 5.70 (d, J=6.8 Hz, 1H),5.15 (d, J=10.1 Hz, 1H), 5.14-5.07 (m, 1H), 4.95 (d, J=16.6 Hz, 1H),4.83 (t, J=6.7 Hz, 2H), 4.71 (s, 2H), 2.54 (dd, J=24.9, 12.6 Hz, 2H),2.30 (d, J=11.2 Hz, 1H), 2.18 (d, J=13.5 Hz, 1H), 2.02 (d, J=12.9 Hz,1H), 1.96-1.80 (m, 2H), 1.78 (d, J=16.1 Hz, 1H), 1.49 (dd, J=26.4, 11.2Hz, 2H);

its ¹H NMR (400 MHz, Methanol-d₄) is δ 8.85 (d, J=1.1 Hz, 1H), 8.05 (td,J=7.9, 4.8 Hz, 1H), 7.96-7.86 (m, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.59(ddd, J=9.2, 4.6, 2.3 Hz, 2H), 7.25-7.19 (m, 1H), 7.19-7.11 (m, 1H),5.78 (ddt, J=16.5, 10.1, 6.1 Hz, 1H), 5.12-5.07 (m, 2H), 5.06 (t, J=1.3Hz, 1H), 4.98 (dd, J=17.0, 1.4 Hz, 1H), 4.90 (d, J=1.4 Hz, 2H),4.25-4.19 (m, 1H), 4.14 (dd, J=14.1, 7.1 Hz, 1H), 2.34-2.12 (m, 2H),2.07 (dd, J=17.0, 4.1 Hz, 1H), 1.99-1.82 (m, 1H), 1.74-1.65 (m, 2H),1.65-1.53 (m, 2H), 1.31 (d, J=4.2 Hz, 3H), 1.29-1.25 (m, 2H);

its ¹H NMR (400 MHz, Methanol-d₄) is δ 8.84 (s, 1H), 8.05 (t, J=7.9 Hz,1H), 7.92 (d, J=8.1 Hz, 1H), 7.66 (dd, J=7.6, 0.9 Hz, 1H), 7.63-7.53 (m,2H), 7.22-7.14 (m, 2H), 5.84-5.74 (m, 1H), 5.10-5.07 (m, 2H), 5.06 (q,J=1.3 Hz, 1H), 4.98 (dq, J=17.0, 1.4 Hz, 1H), 4.89 (dt, J=6.1, 1.4 Hz,2H), 2.71 (d, J=6.9 Hz, 1H), 2.59 (s, 1H), 2.24 (dd, J=16.4, 7.8 Hz,2H), 2.04 (d, J=8.5 Hz, 1H), 1.73 (td, J=10.9, 6.8 Hz, 6H); scheme C:

scheme D:

(I-1-1), its ¹H NMR (400 MHz, MeOD) is δ 8.85 (s, 1H), 8.46 (s, 2H),7.99 (t, J=7.9 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.65 (dd, J=16.6, 8.1Hz, 3H), 7.22 (d, J=8.6 Hz, 2H), 5.73 (ddt, J=16.3, 10.2, 6.1 Hz, 1H),5.05 (dd, J=10.3, 1.1 Hz, 1H), 4.93 (dd, J=17.1, 1.3 Hz, 1H), 4.82 (d,J=6.1 Hz, 2H), 2.90 (s, 6H), 2.60 (d, J=8.4 Hz, 1H), 2.21 (s, 2H), 2.10(d, J=10.6 Hz, 2H), 1.70 (d, J=11.4 Hz, 4H), 1.59 (s, 6H);

(I-1-2), its ¹H NMR (400 MHz, CDCl₃) is δ 8.86 (s, 1H), 8.54 (s, 1H),7.95 (t, J=7.9 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H),7.43 (d, J=7.6 Hz, 1H), 7.32 (d, J=8.5 Hz, 2H), 5.72 (ddt, J=16.5, 10.3,6.2 Hz, 1H), 5.06 (d, J=10.2 Hz, 1H), 4.95 (dd, J=17.1, 1.0 Hz, 1H),4.75 (d, J=6.1 Hz, 2H), 3.05 (m, 1H), 2.93 (m, 1H), 2.68 (s, 6H), 2.32(m, 2H), 1.84 (m, 6H), 1.60 (s, 6H);

(I-3-1), its ¹H NMR (400 MHz, CDCl₃) is δ 8.87 (s, 1H), 7.90 (t, J=7.9Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.39 (dd,J=7.6, 0.5 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 5.72 (ddt, J=16.4, 10.2, 6.2Hz, 1H), 5.06 (dd, J=10.2, 1.0 Hz, 1H), 4.95 (dd, J=17.1, 1.2 Hz, 1H),4.76 (d, J=6.2 Hz, 2H), 4.04 (s, 1H), 2.66 (m, 4H), 2.58-2.47 (m, 1H),2.16 (m, 4H), 1.96 (m, 2H), 1.87-1.78 (m, 4H), 1.60 (s, 6H), 1.58-1.39(m, 4H);

(I-3-2), its ¹H NMR (400 MHz, CDCl₃) is δ 8.87 (s, 1H), 7.92 (t, J=7.9Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.38 (d, J=7.6Hz, 1H), 7.29 (t, J=4.2 Hz, 2H), 5.79-5.66 (m, 1H), 5.06 (dd, J=10.2,1.0 Hz, 1H), 4.96 (dd, J=17.1, 1.2 Hz, 1H), 4.77 (d, J=6.2 Hz, 2H), 4.02(s, 1H), 2.70-2.50 (m, 5H), 2.26 (s, 1H), 1.98 (m, 4H), 1.82 (s, 4H),1.69-1.56 (m, 10H);

(I-8-1), its ¹H NMR (400 MHz, CDCl₃) is δ 8.86 (s, 1H), 7.93-7.85 (m,1H), 7.78 (d, J=7.8 Hz, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.39 (dd, J=7.6,0.7 Hz, 1H), 7.19 (d, J=8.5 Hz, 2H), 5.71 (ddt, J=16.4, 10.2, 6.2 Hz,1H), 5.05 (dd, J=10.2, 1.1 Hz, 1H), 4.94 (dd, J=17.1, 1.3 Hz, 1H), 4.77(d, J=6.2 Hz, 2H), 4.11 (d, J=8.9 Hz, 1H), 3.24 (t, J=7.0 Hz, 4H),2.52-2.43 (m, 1H), 2.14-2.00 (m, 3H), 1.92 (d, J=11.2 Hz, 4H), 1.60 (s,6H), 1.45 (dt, J=14.9, 7.5 Hz, 2H), 1.23-1.08 (m, 2H);

(I-8-2), its ¹H NMR (400 MHz, CDCl₃) is δ8.87 (s, 1H), 7.92 (d, J=7.8Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.39 (d, J=7.6Hz, 1H), 7.29-7.25 (m, 2H), 5.82-5.63 (m, 1H), 5.12-4.91 (m, 2H), 4.78(d, J=6.2 Hz, 2H), 4.01 (s, 1H), 3.17 (s, 4H), 2.53 (s, 1H), 2.33 (s,1H), 2.06 (d, J=4.4 Hz, 2H), 1.89 (d, J=11.6 Hz, 2H), 1.75 (d, J=14.1Hz, 2H), 1.59 (d, J=17.2 Hz, 8H), 1.46 (t, J=13.1 Hz, 2H);

(I-15-1), its ¹H NMR (400 MHz, MeOD) is δ 8.84 (s, 1H), 8.04 (t, J=7.9Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.60 (d, J=8.6Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 5.78 (ddt, J=16.3, 10.3, 6.1 Hz, 1H),5.12-5.05 (m, 3H), 4.98 (dd, J=17.1, 1.3 Hz, 1H), 4.89 (d, J=6.1 Hz,2H), 4.84 (s, 2H), 3.68 (s, 2H), 2.97-2.86 (m, 1H), 2.66 (s, 6H),2.60-2.50 (m, 1H), 2.15 (d, J=8.6 Hz, 2H), 2.04 (d, J=9.0 Hz, 2H),1.66-1.54 (m, 4H);

(I-15-2), its ¹H NMR (400 MHz, MeOD) is δ 8.83 (s, 1H), 8.04 (t, J=7.9Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.67-7.62 (m, 1H), 7.59 (d, J=8.6 Hz,2H), 7.29 (d, J=8.5 Hz, 2H), 5.76 (ddt, J=16.3, 10.2, 6.1 Hz, 1H),5.10-5.02 (m, 3H), 4.96 (dd, J=17.1, 1.3 Hz, 1H), 4.87 (d, J=6.8 Hz,2H), 4.82 (d, J=6.8 Hz, 2H), 2.73 (d, J=4.2 Hz, 1H), 2.29 (d, J=21.9 Hz,7H), 2.04-1.90 (m, 4H), 1.66 (dd, J=15.6, 6.1 Hz, 4H);

(I-36-1), its ¹H NMR (400 MHz, CDCl₃) is δ 8.88 (d, J=2.6 Hz, 1H), 8.09(dd, J=15.0, 7.8 Hz, 1H), 7.99-7.83 (m, 2H), 7.54 (t, J=9.5 Hz, 2H),7.39 (d, J=8.7 Hz, 1H), 7.21 (d, J=8.5 Hz, 1H), 5.74 (dq, J=10.5, 5.9Hz, 1H), 5.12 (t, J=8.8 Hz, 3H), 4.99 (d, J=17.1 Hz, 1H), 4.80 (d, J=6.3Hz, 2H), 4.67 (d, J=6.0 Hz, 2H), 3.39-3.24 (m, 4H), 2.60-2.34 (m, 3H),2.14 (dt, J=14.0, 6.8 Hz, 3H), 1.96 (d, J=10.8 Hz, 4H), 1.55-1.37 (m,2H), 1.27-1.12 (m, 2H);

(I-36-2), its ¹H NMR (400 MHz, MeOD) is δ 8.86 (s, 1H), 8.02 (dt,J=24.0, 7.9 Hz, 3H), 7.64 (dd, J=27.1, 8.1 Hz, 3H), 7.27 (t, J=8.6 Hz,2H), 7.01-6.91 (m, 3H), 6.72-6.64 (m, 3H), 5.79 (ddd, J=16.3, 11.2, 6.1Hz, 1H), 5.10-5.05 (m, 2H), 4.85 (d, J=6.8 Hz, 2H), 2.57 (d, J=10.7 Hz,1H), 2.48-2.28 (m, 3H), 2.23-2.06 (m, 3H), 1.98-1.71 (m, 6H), 1.58 (dd,J=23.2, 12.9 Hz, 3H), 1.44 (ddd, J=16.1, 13.2, 3.5 Hz, 2H), 1.19-1.00(m, 2H);

(I-41-1), its ¹H NMR (400 MHz, Chloroform-d) is δ 9.00 (s, 1H), 8.30 (d,J=8.6 Hz, 1H), 8.22 (d, J=2.4 Hz, 1H), 7.96 (t, J=7.9 Hz, 1H), 7.73 (dd,J=8.1, 0.8 Hz, 1H), 7.55 (dd, J=8.7, 2.4 Hz, 1H), 7.44 (dd, J=7.7, 0.8Hz, 1H), 5.77-5.66 (m, 1H), 5.12-5.05 (m, 1H), 4.97 (dq, J=17.0, 1.4 Hz,1H), 4.76 (dt, J=6.3, 1.3 Hz, 2H), 2.70 (s, 1H), 2.56 (s, 6H), 2.23 (q,J=9.5 Hz, 4H), 2.11-2.01 (m, 4H), 1.58 (t, J=10.3 Hz, 6H);

(I-41-2), its ¹H NMR (400 MHz, Chloroform-d) is δ8.99 (s, 1H), 8.54 (s,1H), 8.32 (d, J=8.7 Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.10 (t, J=7.7 Hz,1H), 7.92 (s, 1H), 7.78 (dd, J=8.1, 0.8 Hz, 1H), 7.47-7.41 (m, 1H),5.79-5.71 (m, 1H), 5.08 (dq, J=10.1, 1.2 Hz, 1H), 4.97 (dq, J=17.0, 1.3Hz, 1H), 4.77 (dt, J=6.2, 1.4 Hz, 2H), 3.99 (s, 1H), 2.75 (d, J=11.0 Hz,1H), 2.52 (s, 6H), 2.32-2.18 (m, 1H), 2.09 (d, J=14.4 Hz, 4H), 1.31 (d,J=22.8 Hz, 4H); wherein,

means that the cis-trans conformation is uncertain; scheme E:

(I-8-1), its ¹H NMR (400 MHz, CDCl₃) has a peak of 1.23-1.08; wherein,

means that the cis-trans conformation is uncertain; scheme F:

(I-1-1) with a retention time of 10.55 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→50% mobile phase B;

(I-1-2) with a retention time of 10.78 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→50% mobile phase B;

(I-3-1) with a retention time of 11.01 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→50% mobile phase B;

(I-3-2) with a retention time of 11.20 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→50% mobile phase B;

(I-8-1) with a retention time of 10.78 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→50% mobile phase B;

(I-8-2) with a retention time of 11.00 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→50% mobile phase B;

(I-15-1) with a retention time of 7.02 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→95% mobile phase B;

(I-15-2) with a retention time of 7.16 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→95% mobile phase B;

(I-36-1) with a retention time of 7.14 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→95% mobile phase B;

(I-36-2) with a retention time of 7.15 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B-95% mobile phase B;

(I-41-1) with a retention time of 6.17 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→95% mobile phase B;

(I-41-2) with a retention time of 6.28 min under the followingconditions: Agilent 1260 high performance liquid chromatograph; mobilephase A: water (0.1% formic acid), mobile phase B: acetonitrile; columntime: 15 min; column type: Waters' Xselect, 5 μm, 4.6×250 mm; gradientelution, 5% mobile phase B→95% mobile phase B; wherein,

means that the cis-trans conformation is uncertain; scheme G:


13. A preparation method of the pyrazolone-fused pyrimidine compoundrepresented by formula II according to claim 1, the method is any of thefollowing methods: method 1, comprising the following steps: step I,oxidizing compound II-1A by an oxidant in an organic solvent to obtaincompound II-1B; step II, reacting compound II-1B with compound II-1C inan organic solvent and under alkaline conditions to obtain compound II;

method 2, comprising the following steps: step I, hydrolyzing compoundII-2A (R¹ is —(C═O)—O—C₂H₅) to obtain compound II-2B (R¹ is —(C═O)—OH);step II, a condensation reaction is carried out between compound II-2Band an amino compound in an organic solvent to obtain compound II (R¹ is—(C═O)—NR¹⁻⁵⁻¹R¹⁻⁵⁻²);


14. A compound represented by formula II-1C:

wherein, X is CH or N, A is as defined in claim
 1. 15. A compoundrepresented by formula II-1C:

wherein, X is CH or N, A is as defined in claim 1; the compoundrepresented by formula II-1C is a compound represented by formula 1C:

wherein, A is C₃-C₂₀ cycloalkyl substituted by one R¹, R¹ is —NR¹⁻³R¹⁻⁴or —C(═O)R¹⁻⁵, and R¹⁻³, R¹⁻⁴ and R¹⁻⁵ are as defined above.
 16. Thecompound represented by formula II-1C according to claim 14, wherein,the compound is any one of the compounds described in any of thefollowing schemes: scheme a:

scheme b:

its ¹H NMR (400 MHz, CDCl₃) is δ 7.08-6.96 (m, 2H), 6.70-6.60 (m, 2H),3.57 (s, 2H), 3.22 (t, J=7.0 Hz, 4H), 2.38 (tt, J=12.1, 3.2 Hz, 1H),2.15-1.95 (m, 5H), 1.95-1.81 (m, 4H), 1.51-1.30 (m, 2H), 1.21-1.04 (m,2H); or,

its ¹H NMR (400 MHz, MeOD) is δ 7.10-6.97 (m, 2H), 6.74-6.63 (m, 2H),4.22-4.08 (t, J=8.0 Hz, 4H), 3.47-3.38 (m, 1H), 2.61-2.52 (m, 1H),2.52-2.28 (m, 2H), 1.92-1.62 (m, 8H).
 17. A method for inhibiting WEE1kinase in a subject, comprising administering a therapeuticallyeffective amount of a substance X to the subject; the substance X is thepyrazolone-fused pyrimidine compound represented by formula II accordingto claim 1, the pharmaceutically acceptable salt thereof, the solvatethereof, the solvate of the pharmaceutically acceptable salt thereof,the metabolite thereof or the prodrug thereof.
 18. A pharmaceuticalcomposition comprising the substance X and a pharmaceutical excipient;the substance X is the pyrazolone-fused pyrimidine compound representedby formula II according to claim 1, the pharmaceutically acceptable saltthereof, the solvate thereof, the solvate of the pharmaceuticallyacceptable salt thereof, the metabolite thereof or the prodrug thereof.19. A combination comprising a substance X and an anticancer drug, thesubstance X is the pyrazolone-fused pyrimidine compound represented byformula II according to claim 1, the pharmaceutically acceptable saltthereof, the solvate thereof, the solvate of the pharmaceuticallyacceptable salt thereof, the metabolite thereof or the prodrug thereof.20-24. (canceled)
 25. A method for treating and/or preventing diseasesor cancers related to WEE1 kinase comprising administering atherapeutically effective amount of the substance X to a patient; thesubstance X is the pyrazolone-fused pyrimidine compound represented byformula II according to claim 1, the pharmaceutically acceptable saltthereof, the solvate thereof, the solvate of the pharmaceuticallyacceptable salt thereof, the metabolite thereof or the prodrug thereof.26. (canceled)